Study protocol for a national cohort of adults focused on respiratory health: the American Lung Association Lung Health Cohort (ALA-LHC) Study

Abstract

Introduction
The current framework for investigating respiratory diseases is based on defining lung health as the absence of lung disease. In order to develop a comprehensive approach to prevent the development of lung disease, there is a need to evaluate the full spectrum of lung health spanning from ideal to impaired lung health. The American Lung Association (ALA) Lung Health Cohort is a new, population-based, cohort study focused primarily on characterising lung health in members of the millennial generation without diagnosed severe respiratory disease. Participants will be enrolled for the baseline study visit starting in 2021, and funding will be sought to support future study exams as part of a longitudinal cohort study. This study will be crucial for developing a novel paradigm of lung health throughout the adult life course.

Methods and analysis
This study will leverage the existing infrastructure of the ALA Airways Clinical Research Centers network to enrol 4000 participants between ages 25 and 35 years old at 39 sites across the USA between April 2021 and December 2024. Study procedures will include physical assessment, spirometry, chest CT scan, accelerometry and collection of nasal epithelial lining fluid, nasal epithelial cells, blood and urine. Participants will complete questionnaires about their sociodemographic characteristics, home address histories and exposures, work history and exposure, medical histories, lung health and health behaviours and activity.

Ethics and dissemination
The study was approved by the Johns Hopkins Medicine Institutional Review Board. Findings will be disseminated to the scientific community through peer-reviewed journals and at professional conferences. The lay public will receive scientific findings directly through the ALA infrastructure including the official public website. Deidentified datasets will be deposited to BioLINCC, and deidentified biospecimens may be made available to qualified investigators along with a limited-use datasets.

Full text

1
ReyfmanPA, etal. BMJ Open 2021;11:e053342. doi:10.1136/bmjopen-2021-053342
Open access
Study protocol for a national cohort of
adults focused on respiratory health: the
American Lung Association Lung
Health Cohort (ALA- LHC) Study
Paul A Reyfman ,1 Elizabeth Sugar,2 Heather Hazucha,3 Jenny Hixon,1
Curt Reynolds,2 Sonali Bose,4 Mark T Dranseld,5 MeiLan K Han,6
Raul San Jose Estepar,7,8 Mary B Rice,9,10 George R Washko,8,11
Mercedes Carnethon,12 Ravi Kalhan ,1,12 American Lung Association Airways
Clinical Research Network
To cite: ReyfmanPA, SugarE,
HazuchaH, etal. Study
protocol for a national cohort of
adults focused on respiratory
health: the American Lung
Association Lung Health Cohort
(ALA- LHC) Study. BMJ Open
2021;11:e053342. doi:10.1136/
bmjopen-2021-053342
►Prepublication history for
this paper is available online.
To view these les, please visit
the journal online (http:// dx. doi.
org/ 10. 1136/ bmjopen- 2021-
053342).
PAR and ES contributed equally.
Received 12 May 2021
Accepted 23 June 2021
For numbered afliations see
end of article.
Correspondence to
Dr Ravi Kalhan;
r- kalhan@ northwestern. edu
Protocol
© Author(s) (or their
employer(s)) 2021. Re- use
permitted under CC BY- NC. No
commercial re- use. See rights
and permissions. Published by
BMJ.
ABSTRACT
Introduction The current framework for investigating
respiratory diseases is based on dening lung health
as the absence of lung disease. In order to develop a
comprehensive approach to prevent the development of
lung disease, there is a need to evaluate the full spectrum
of lung health spanning from ideal to impaired lung health.
The American Lung Association (ALA) Lung Health Cohort
is a new, population- based, cohort study focused primarily
on characterising lung health in members of the millennial
generation without diagnosed severe respiratory disease.
Participants will be enrolled for the baseline study visit
starting in 2021, and funding will be sought to support
future study exams as part of a longitudinal cohort study.
This study will be crucial for developing a novel paradigm
of lung health throughout the adult life course.
Methods and analysis This study will leverage the
existing infrastructure of the ALA Airways Clinical Research
Centers network to enrol 4000 participants between ages
25 and 35 years old at 39 sites across the USA between
April 2021 and December 2024. Study procedures will
include physical assessment, spirometry, chest CT scan,
accelerometry and collection of nasal epithelial lining uid,
nasal epithelial cells, blood and urine. Participants will
complete questionnaires about their sociodemographic
characteristics, home address histories and exposures,
work history and exposure, medical histories, lung health
and health behaviours and activity.
Ethics and dissemination The study was approved by the
Johns Hopkins Medicine Institutional Review Board. Findings
will be disseminated to the scientic community through peer-
reviewed journals and at professional conferences. The lay
public will receive scientic ndings directly through the ALA
infrastructure including the ofcial public website. Deidentied
datasets will be deposited to BioLINCC, and deidentied
biospecimens may be made available to qualied investigators
along with a limited- use datasets.
INTRODUCTION AND RATIONALE
Developing a robust approach to lung disease
prevention requires a broad definition of
lung health.1 While the respiratory research
community implicitly construes lung health
as the absence of overt lung disease, the
cardiovascular (CV) community has explic-
itly delineated a continuum ranging from
ideal health to impaired health to estab-
lished disease. According to this framework,
CV health is composed of a set of factors,
including several that directly occur along the
causal pathway from health to disease. This
paradigm of CV health serves as a foundation
for developing preventive health measures
by targeting risk factors for loss of health
and recognition of measurable intermediate
endotypes, such as heightened inflammation
and hypercholesterolaemia.
Strengths and limitations of this study
►This is the rst large, prospective US cohort study of
respiratory health over the adult life course.
►Lung health outcomes are dened broadly and in-
clude respiratory symptoms, physiological lung
function and CT scan- dened lung and airways
injury.
►A wide array of biospecimens including blood, urine
and nasal samples will be collected at the baseline
assessment, which will allow for discovery of bio-
markers of impaired respiratory health.
►Individuals will provide extensive information on
modiable exposures and risk factors (eg, lifetime
air pollution, potentially noxious inhalation exposure
such as marijuana and e- cigarettes, reduced physi-
cal activity and workplace exposures), which will be
updated throughout the course of follow- up.
►Current funding supports only a cross- sectional ex-
amination and remote follow- up contacts; additional
funding will be required for future in- person study
exams and the ascertainment of long- term lung
health outcomes.
on July 6, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2021-053342 on 5 July 2021. Downloaded from

2ReyfmanPA, etal. BMJ Open 2021;11:e053342. doi:10.1136/bmjopen-2021-053342
Open access
The American Lung Association Lung Health Cohort
(ALA- LHC) Study is motivated by the conviction that a
large, population- based cohort of young adults focused on
the respiratory system is needed to define the constructs
of of ‘ideal’ versus ‘impaired’ lung health. Previous
studies of subclinical lung disease have examined healthy
controls in disease- focused studies or used limited
information about respiratory symptoms, physiology or
imaging derived from cohort studies focused on other
chronic conditions. Existing prospective cohort studies
within the respiratory field have a maximum follow- up of
10 years and are focused on specific respiratory diseases,
such as asthma and chronic obstructive pulmonary disease
(COPD). Life course studies of lung health are necessary
to describe how an individual progresses from ideal lung
health to an intermediate phenotype of impaired lung
health and ultimately to chronic lung disease.
We have developed a conceptual paradigm of lung
health according to which there are two fundamental
forms of impaired lung health: (1) impaired ‘reserve’ or
lower peak lung function in young adult and (2) ‘suscep-
tibility’ to impaired lung health or accelerated decline
in lung function from young adulthood to middle age.
The ALA- LHC will focus on modifiable exposures and
clinical and behavioural risk factors in members of the
millennial generation that we hypothesise are associated
with impaired lung health reserve and on biomarkers of
susceptibility to future lung disease. Identifying the factors
associated with reserve and susceptibility will enhance the
depiction of the continuum of lung health and will facili-
tate designing novel prevention strategies.
Specic aims
Our long- term goal is to determine factors evident
in early adulthood that influence risk for future lung
disease through detailed assessments of modifiable and
non- modifiable environmental, clinical and behavioural
risk factors and responses (physiological, imaging- based
and biological including the nasal epithelial transcrip-
tome). Our motivations were bolstered by a call from
the National Heart, Lung, and Blood Institute (NHLBI)
for the development of new epidemiology cohorts to
address research hypothesis that were beyond the scope
of existing cohorts.2 We have observed that impaired
lung health (lower lung function, self- report of respi-
ratory symptoms and lung abnormalities on chest CT
scan) precedes the development of chronic lung disease.
Therefore, the focus of the initial contact will be to estab-
lish the cohort, characterise their current lung health and
test hypotheses about the risk factors and manifestations
of impaired lung health in young adults. There are three
specific aims:
1. Determine whether modifiable exposures and risk fac-
tors (lifetime air pollution, potentially noxious inha-
lational exposures such as marijuana and e- cigarettes
and reduced physical activity) are associated with lower
lung function and greater burden of respiratory symp-
toms in young adults.
2. Determine whether CT measurements of small airway
and parenchymal lung abnormalities are associated
with lower lung function and greater burden of respi-
ratory symptoms in young adults.
3. Collect and store biospecimens for future analyses to
determine the association between the nasal respira-
tory epithelial transcriptome and selected blood bio-
markers, CT measured small airway abnormality and
parenchymal lung abnormalities in young adults.
Remote contacts will be used to keep the cohort
engaged, update contact information and collect
short- term follow- up information on the exposures
and responses. We will endeavour to secure additional
funding for future in- person exams and the evaluation of
biospecimens.
METHODS AND ANALYSIS
Study design
The ALA- LHC is a longitudinal, multicentre cohort study
that will enrol approximately 4000 participants aged
25–35 years old who do not have a diagnosis of severe
lung disease recruited at participating research sites
across the USA.
Patient and public involvement
The ALA- LHC was conceived and designed through close
collaboration with the ALA, which regularly solicits input
for its research programmes from participating patient
advisory groups. Patients were not explicitly involved in
the design of the ALA- LHC. The ALA will participate in
the dissemination of results to the community of stake-
holders interested in respiratory disease.
Eligibility criteria
Eligibility is deliberately broad and selected to be inclusive
of young adults with a range of exposures that may influ-
ence lung health. However, individuals with established
moderate- to- severe lung disease will not be enrolled. The
detailed inclusion and exclusion criteria are provided in
table 1.
Outcomes
The primary outcome measures are as follows:
►In- person spirometry: Prebronchodilator lung func-
tion (forced expiratory volume in 1 s (FEV1), forced
vital capacity (FVC) and peak flow) measured in
accordance with the American Thoracic Society
(ATS)/European Respiratory Society (ERS) stand-
ards and using United States National Health and
Nutrition Examination Survey (NHANES) reference
values.3 4
The primary outcome measures are as follows:
– Prebronchodilator FEV1.
– Prebronchodilator FVC.
►ATS- Division of Lung Diseases (DLD) Respiratory
Questionnaire: The ATS- DLD is a general respiratory
symptom questionnaire. We will use the Lung Health
on July 6, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2021-053342 on 5 July 2021. Downloaded from

3
ReyfmanPA, etal. BMJ Open 2021;11:e053342. doi:10.1136/bmjopen-2021-053342
Open access
Study (LHS- III) modified version that includes infor-
mation regarding occupational exposures and asthma:
– Any symptoms
– Individual symptoms
►CT measurements of small airway and parenchymal
lung abnormalities will be made using both commer-
cially available and open- source software (Chest
Imaging Platform, an National Institutes of Health
(NIH)- funded, open source platform, http://www.
chestimagingplatform. org).5 The primary outcome
measurements are as follows:
– Extent of parametric response map for functional
small airways disease (PRMfSAD).
– Size of structural abnormalities (expressed as the
percent of total lung with that classification (eg,
50% emphysema))
Recruitment
Participants will be recruited at each ALA Airways Clinical
Research Centers (ACRC) site (box 1) through public
advertising campaigns (digitally and through traditional
media), public outreach, word of mouth and partnerships
with community organisations. Information for potential
and current participants will be posted on a publicly avail-
able study website hosted by the ALA, which will also orga-
nise a social media campaign.
The goal is to recruit a population that is balanced
in terms of sex (target: 1/2 men and 1/2 women) and
educational attainment (target: 1/3 high school educa-
tion or less, 1/3 some college and 1/3 college degree or
higher). Balancing recruitment by education as a proxy
for socioeconomic status (SES) is based on data demon-
strating individual behavioural factors (eg, occupation,
smoking and physical activity) are associated with lung
health and strongly correlated with SES.6 7 Individuals
with lower levels of education are more likely to reside
in lower- income communities, which will also encourage
a distribution of environmental exposures. Although the
recruitment targets are based on SES rather than race,
we do anticipate recruiting a diverse population, with an
expected racial distribution of approximately 60% Cauca-
sian, 30% African American, 7.5% Asian, 2.5% others and
25% Hispanic/Latinx.
Enrolment
To initiate an in- person enrolment, a site will schedule
an initial, in- person visit with the potential participant.
All participants will provide written informed consent.
The procedures and questionnaires are expected to take
approximately 4 hours. Young adults often have conflicts
(eg, need for childcare and limited time off) that would
make it difficult to schedule such a large block of time.
In order to make the initial assessment more feasible, the
in- person visit may be broken up into several shorter visits
with emphasis on completing as many of the assessments
remotely as possible to reduce the in- person time. The
Table 1 Inclusion and exclusion criteria
Inclusion Exclusion
Age 25–35 years old at the time of the enrolment Severe asthma that is dened as any of the following:
►Current Global Initiative for Asthma Step 4 or higher therapy27
OR
►Three or more unscheduled healthcare visits (provider/urgent
care/ER) for asthma in the past 12 months
OR
►One asthma hospitalisation in the past 12 months
Able to read and understand English or Spanish History of any chronic lung disease other than asthma including but
not limited to COPD, cystic brosis, pulmonary brosis, pulmonary
hypertension or congenital lung disease
Has and is willing to share a social security number Current pregnancy
Resident (citizen or non- citizen) of the USA for at least 12
months prior to examination
History of cancer other than non- melanoma skin cancer
Willing to provide contact information for at least two
proxies who are likely to know the whereabouts and vital
status of the participant
Diagnosed cardiovascular disease (ie, congenital heart disease and
coronary heart disease)
History of cancer other than non- melanoma skin cancer
Inability to comply with study procedures
Any condition that puts the participant at risk by participating in
the study as deemed by study investigators (eg, serious respiratory
illness requiring antibiotics or steroids or severe fever at the time of
the study visit)
Institutionalisation
COPD, chronic obstructive pulmonary disease; ER, emergency room.
on July 6, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2021-053342 on 5 July 2021. Downloaded from

4ReyfmanPA, etal. BMJ Open 2021;11:e053342. doi:10.1136/bmjopen-2021-053342
Open access
first part of the in- person visit will focus on evaluating
eligibility and obtaining informed consent for participa-
tion in the ALA- LHC. The procedures and key question-
naires relating to the primary aims of the study must be
completed in person. The remaining questionnaires may
be completed remotely.
Study data collection
Baseline assessment
The baseline assessment includes an in- person evalua-
tion, wearable device monitoring of activity and remote
contacts. Box 2 lists the procedures and questionnaire
data collection for the baseline assessment. The total time
allocated for the completion of all procedures and ques-
tionnaires is 4 hours. The goal is to collect all assessments
within 1 month (28 days of enrolment); however, due to
potential barriers to that collection schedule related to
the ongoing COVID-19 pandemic, the permitted time
interval for evaluations following initial enrolment may
be longer.
In-person activities
Individuals will be consented, tested for eligibility and
enrolled at the beginning of the in- person evaluation.
All procedures except for the actigraphy monitoring and
home spirometry will be performed in the clinic. In addi-
tion, key questionnaires will be completed during the
in- person visit.
In-home activities
Additional in- home activities are planned to collect infor-
mation on lung function, activity and vaping after the
in- person visit. Each participant will be asked to complete
a home spirometry session on five separate days over a
14- day period within a month of the in- person visit with
coaching from a site coordinator via a telemedicine visit.
In addition, each participant will be asked to wear an
activity monitor for 1 week and then mail it back to the
site. Those individuals who indicated that they have used
e- cigarettes and vaping or heat- not- burn (HNB)/heated
tobacco devices will be asked to complete a 1- week daily
diary recording the type and frequency of e- cigarette,
vaping or HNB product use and any related symptoms.
Remote contact activities
Remote contacts will be used to facilitate the completion
of the baseline assessment. Questionnaires that are not
completed during the in- person visit will be completed
remotely (eg, online by the participant using a link sent
via email, text message, mail or phone).
Box 1 American Lung Association (ALA) Lung Health
Cohort study sites and cores
Study sites
►Baylor College of Medicine—Houston, Texas.
►Duke University consortium:
– Duke University Medical Center—Durham, North Carolina.
– Johns Hopkins University.
– University of North Carolina Hospital.
►Michigan consortium:
– University of Michigan—Ann Arbor, Michigan.
– University of Iowa.
►Illinois consortium:
– Northwestern University.
– Rush University.
– University of Chicago.
– University of Illinois at Chicago.
►Pacic Northwest consortium:
VA Puget Sound Health Care System—Seattle, Washington.
►Temple University consortium:
– Temple Lung Center—Philadelphia, Pennsylvania.
– Ohio State University—Wexner Medical Center.
– University of Pittsburgh—Emphysema COPD Research Center.
– Medical University of South Carolina.
►Nemours Children’s Health consortium:
– Nemours Children’s Health—Jacksonville, Florida.
– University of Florida, Jacksonville.
►National Jewish Health consortium:
– National Jewish Health—Denver, Colorado.
– University of Colorado Anschutz Medical Campus.
– Mount Sinai, New York City.
►Northern New England consortium:
– University of Vermont—Burlington, Vermont.
– University of Rochester.
►New York consortium:
– Columbia University, New York, New York.
– Brigham and Women’s Hospital.
– New York Medical College.
– Presbyterian Brooklyn Methodist Hospital.
– Cornell University.
– New York University.
►The UAB Lung Health Center—Birmingham, Alabama.
►University of Kansas consortium:
– University of Kansas Medical Center.
– Wake Forest School of Medicine.
– Vanderbilt University Medical Center.
– University of Wisconsin Madison.
►St Vincent Hospital and Health Care Center—Indianapolis, Indiana.
►University of California consortium:
– University of California, San Francisco.
– University of California, Los Angeles.
►University of Arizona—Tucson, Arizona.
Study cores.
►Administrative Core at Northwestern University.
►Actigraph Reading Center at Northwestern University.
►Data Coordinating Center at Johns Hopkins University.
►Spirometry Reading Center at Johns Hopkins University.
►Imaging Core at Brigham and Women’s Health and University of
Michigan.
Continued
Box 1 Continued
►ALA Airways Clinical Research Centers (ACRC) Biorepository at
Nemours Children’s Hospital.
►Environmental Exposure Core at Beth Israel Deaconess Medical
Center.
on July 6, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2021-053342 on 5 July 2021. Downloaded from

5
ReyfmanPA, etal. BMJ Open 2021;11:e053342. doi:10.1136/bmjopen-2021-053342
Open access
Remote follow-up
During follow- up, participants will be contacted remotely
(eg, via text message, email, mail or phone) every 3–6
months and asked to update their contact information
and complete additional assessments related to the
topics described above for the in- person visit (eg, lung
health and behavioural habits) as well as health events
(eg, urgent care visits, hospitalisation, vaccinations and
diagnoses). In conjunction with each of the follow- up
contacts, participants will be asked to schedule and
complete a single, coached home spirometry session.
Study procedures
Questionnaires
Questionnaires may be completed in multiple ways.
During the study visit, forms will be either directly data
entered into the ALA- LHC REDCap data repository on
tablets provided by the study or on paper forms, which
will later be data entered by the site staff.
Environmental evaluation
The Environmental Exposure Core will use the lifetime
address history of each participant to perform geocoding.
The geocodes will be used to link relevant exposure data
to each participant. Exposure data will include long- term
averages of residential air pollution exposure (elemental
carbon, organic carbon, nitrogen dioxide and sulfates),
fine particulate matter (PM2.5),8–10 ozone, census- tract
level indicators of neighbourhood socioeconomic posi-
tion (median household income, median home value,
measures of household crowding and distribution of
education level) and weather data.
Spirometry at the study site
Prebronchodilator spirometry will be performed at the
in- person baseline visit if local conditions and policies
permit it. Each site will follow their institutional guide-
lines for conduct of research and COVID-19- related
precautions and procedures and, if required at their local
institution, institutional review board (IRB) approval.
Spirometry measurements taken at the site will adhere
to ATS/ERS standards.3 Quality control, training and
interpretation of results will be led by the Spirometry
Reading Center at Johns Hopkins University. Spirom-
etry measurements will include the FVC, FEV1 and FEV1/
FVC ratio. Only prebronchodilator spirometry will be
performed (participants will not receive albuterol).
Spirometry reference values will be those of Hankinson et
al from NHANES.4 Spirometry sessions will be performed
by a certified technician.
Home spirometry
All participants will be provided with a Spirobank Smart
spirometer (MIR USA International Research), which is
an Food and Drug Administration 510(k)- cleared device
(K072979) for home use. After the in- person visit, partic-
ipants will be asked to perform home spirometry on five
separate days over a 14- day period within 1 month of the
in- person visit. Therefore, participants will be asked to
complete quarterly home spirometry sessions in conjunc-
tion with the quarterly contacts. The remote spirometry
sessions will be coached by a certified technician using a
video conference link.
Chest CT acquisition
Each participant will undergo CT imaging. CT scan will
be acquired with multidetector CT scanners (64 detector
channels) at full inspiration and expiratory effort using a
Box 2 Activities and data collection
Consent
Eligibility evaluation
Enrolment
Procedures
►Physical assessment (eg, height, weight, resting heart rate and
blood pressure).
►Prebronchodilator spirometry at study site.
►Home spirometry (prebronchodilator).
►Pregnancy testing in participants of childbearing potential (prior to
chest CT).
►Chest CT scan.
►Nasal epithelial lining uid collection (Nasosorption strips).
►Nasal epithelial curettage.
►Phlebotomy (complete blood count, plasma, serum, RNA, DNA and
SARS- CoV-2 serology).
►Urine collection.
►Actigraphy.
Questionnaire domains
►Social security number.
►Contact information for participant and two proxies.
►Home address history.
►Demographics (eg, date of birth, age, race, ethnicity, sex and birth,
gender identity, education, employment status, income and health
insurance coverage).
►Lung health:
– ATS- DLD Respiratory Questionnaire.
– Modied Rhinitis Symptom Utility Index.28
►Substance use (eg, tobacco, e- cigarette/vaping/heat- not- burn, al-
cohol and marijuana).
►Environmental and occupational exposures (eg, secondhand smoke,
pets, mould and fumes).
►Medication use.
►Medical history (eg, disease diagnoses, allergies and pregnancy/
early life factors).
►Activity:
– International Physical Assessment Questionnaire (short form).29
►Sleep:
– Pittsburgh Sleep Quality Instrument.30
►Social elements (eg, neighbourhood safety, social roles and activi-
ties and global health).
►Nutrition.
►COVID-19 history and associated health behaviours (tobacco, e-
cigarettes, hand washing and social distancing).
Patient logs
►Activity log.
►Vaping diary.
on July 6, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2021-053342 on 5 July 2021. Downloaded from

6ReyfmanPA, etal. BMJ Open 2021;11:e053342. doi:10.1136/bmjopen-2021-053342
Open access
low- dose protocol with dose modulation. Imaging recon-
struction will use submillimetre slice thickness with four
reconstructions per scan.
Standardised parameters will be developed for the CT
scanner to be used at each site to ensure consistency of
results. CT scanners at each site will be calibrated using
a standard lung phantom prior to enrolling participants.
All participants will be imaged in the supine body posture
both at full inflation (approximating total lung capacity)
and at the end of forcible exhalation (approximating
residual volume).
Study measurements obtained on the CT scan will
include features based on analyses of the lung parenchyma
through the local histogram to determine lung inflamma-
tion, oedema, emphysema and interstitial changes as well
as the PRMfSAD as has been used previously.11–16
Nasal epithelial curettage
Scraping of the nasal epithelium will be performed using
five passes with the disposable plastic ASI Rhino- Pro
nasal cytology curette from the inferior nasal turbine.
Samples will be immediately frozen in RNA lysis buffer
and stored at −80°C until shipped to the repository for
future processing.
Nasal epithelial lining uid
For collection of nasal epithelial lining fluid, a thin
absorbent, fibrous matrix designed to fit within the nasal
passages (Mucosal Diagnostics Nasosorption FX·i) will
be inserted into each nostril. Participants will be asked
to pinch their nose closed for 1 min prior to removal of
each strip. The two fibrous strips will be placed in sepa-
rate tubes, capped and immediately frozen and stored at
−80°C until shipped to the repository.
Phlebotomy
Approximately 50 mL of blood will be collected by veni-
puncture from the arm or the back of the hand. One
4 mL tube will be transmitted to the local hospital labo-
ratory without processing for measurement of complete
blood count and chemistries. The remaining blood will
be divided into 83 250 uL aliquots of serum and plasma
for freezing and bulk storage pending shipping. One
2.5 mL PAXgene RNA tube will be used to collect blood
for RNA analysis. Also, one lavender tube containing a
remaining pellet after aliquoting plasma will be saved for
DNA analysis. Both these tubes will be stored at −70 or
−80°C until shipped to the repository.
Urine collection
Participants will be instructed on how to obtain a clean
catch urine specimen. A minimum of 20 mL will be
collected from each participant. Urine will be aliquotted
into 10 1 mL non- preserved aliquoting vials and placed at
−80°C for storage until shipment.
Accelerometry
At the conclusion of the in- person visit, participants will
be given the ActiGraph GT3X. At the same time, they will
be given a paper log to record when the device is removed
and put back on and the intervals in which they were
sleeping. Participants will be asked to wear the device on
their non- dominant arm continuously for 24 hours a day
over 7 days after leaving the site and to mail the device
back to the clinic.
COVID-19 exposure and history
Participants will be given a questionnaire to assess self-
reported history of COVID-19 and factors related to
severity of disease. Exposure to SARS- CoV-2 will be
assessed using serology testing.
Data management
Data collection and transfer
Data will be collected, stored and transferred in compli-
ance with Health Insurance Portability and Accountability
Act (HIPAA) Privacy and Security rules.
The primary mechanism for data collection and
management in the ALA- LHC will be REDCap, a secure,
web- based application hosted by the Data Coordinating
Center (DCC) at Johns Hopkins University that can
support direct electronic data entry or forms- based data
capture in compliance with HIPAA Security Rule.17 18 The
ALA- LHS REDCap Project will be managed by the DCC.
The majority of enrolment and study data for the study
visit will be directly entered to REDCap. Tablets will be
provided to each site to facilitate real- time capture of
data elements. However, paper versions of all instruments
will be available as an alternative in case of connectivity
issues, participant preference (in the completion of self-
reported forms) or other barriers to direct data entry. In
addition, each participant will be provided with a tablet to
take home that can be used to complete forms remotely.
Data sharing
The ALA- ACRC DCC has developed and tested proce-
dures for deidentification of personal health information
(PHI) that meet the deidentification standard established
by Section 164.514 of the HIPAA Privacy Rule. Deiden-
tified datasets will be deposited to BioLINCC at sched-
uled milestones (eg, following completion of the baseline
exam by all participants). Deidentified (coded) biospe-
cimens collected in the study that are not analysed may
be made available to qualified investigators along with a
limited- use dataset in line with Office for Human Research
Protections (OHRP) guidelines with a material transfer
agreement and/or data- use agreement as applicable.
Analyses
Hypotheses
There are three primary hypotheses:
►Hypothesis 1: Air pollution and other inhalational
exposures are associated with lower pulmonary
function and more frequent respiratory symptoms,
whereas physical activity is associated with higher
function and less frequent symptoms.
►Hypothesis 2: CT- measured small airways and paren-
chymal lung abnormalities are associated with lower
on July 6, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2021-053342 on 5 July 2021. Downloaded from

7
ReyfmanPA, etal. BMJ Open 2021;11:e053342. doi:10.1136/bmjopen-2021-053342
Open access
pulmonary function and more frequent respiratory
symptoms in young adults.
►Hypothesis 3:
– The pattern of nasal epithelial gene expression is
different in participants with CT- measured small
airways and parenchymal lung abnormalities.
– Blood biomarkers previously associated with dis-
tinct chronic lung diseases such as Interstitial Lung
Disease (ILD) and COPD (fibrinogen, C reactive
protein, soluble receptor for advanced glycosyla-
tion end product, surfactant protein D, club cell
protein-16 and matrix metalloproteinases 7 and
9) are also associated with different CT patterns of
lung abnormalities in young adults.
Hypotheses 1 and 2 will be addressed using data
collected in the main ALA- LHC Study. Specimens will be
collected to enable evaluation of Hypothesis 3 but will be
deferred until additional funding is obtained.
Sample size
Detectable effect sizes were calculated assuming a sample
size of 4000 (assuming 235 per site) and two- sided type
I error rate of 5% (unless otherwise specified). Simula-
tions incorporating a random site effect produced similar
results for variables used in prior ALA- ACRC studies due
to low intraclass correlation coefficient among partici-
pants seen at the same site. Based on prior studies,19–21
we conservatively estimated that the SD of percentage of
predicted FEV1 is to be 15. Data from the Framingham
Study suggest that the SD of long PM2.5 is 1.24 µg/m3 with
an IQR width (IQRw) of approximately 1.87 (ie, the SD
for PM2.5 rescaled in units of IQRw is 0.66). We have 80%
and 90% power to detect 0.98% and 1.13% decreases
in percentage of predicted FEV1 of per IQRw increase
in PM2.5 exposure, a clinically meaningful change as
decreases of 1%–1.5% are associated with all cause
mortality.22 In the Coronary Artery Risk Development in
Young Adults Study, a cohort of 18–30 year olds enrolled
in 1985; baseline symptom prevalence ranged from 10%
(bronchitis) to 45% (wheeze).23 Assuming reference
prevalence of 10%, 15%, 30% and 45%, we have 90%
power to detect an increase in the risk of symptoms to
12%, 17%, 33% and 48% (ie, OR: 1.19, 1.15, 1.12 and
1.11) per IQRw increase in PM2.5.
Primary analyses
The cross- sectional associations between lung health and
modifiable risk factors (Hypothesis 1) and CT measure-
ments (Hypothesis 2), as well as the association between
CT measurements and biological markers (Hypothesis 3),
will be assessed using mixed- effect models with a random
intercept for study site. Robust SEs will be computed
using statistical programme- based approaches when
available and the bootstrap otherwise (eg, absolute risk
differences). During model selection and formal testing,
graphical (eg, residual plots and splines to assess linearity
of the effect of continuous exposures) and analytical (eg,
tests of normality) methods will be used to detect viola-
tions of modelling assumptions.
To evaluate Hypothesis 1, we will examine the cross-
sectional associations of modifiable risk factors (air
pollution exposure, inhalational exposures and physical
activity) with continuous (FEV1 and FVC) and binary
(respiratory symptoms) measurements of lung health. In
addition to the stratification variables, we will adjust all
models for race/ethnicity; body mass index (BMI) (or
height and weight); and, when appropriate, additional
confounders. For environmental exposure, a centred
exposure variable and a centre- specific mean exposure
variable will be used to model within- centre and between-
centre contrasts, or alternatively, centre will be included
as a categorical fixed effect to ensure that there is no
residual confounding.
To evaluate Hypothesis 2, we will examine the cross-
sectional associations of continuous CT measurements
of lung abnormalities (extent of PRMfSAD and percent
lung abnormalities, log transformed if necessary) with
continuous (FEV1 and FVC) and categorical (symptoms)
measurements of lung health. In addition to the stratifi-
cation variables, all models will include age, smoking and
BMI (or height and weight).
To evaluate Hypothesis 3, we will model the association
between blood biomarkers and continuous measures of
lung abnormalities evaluated by CT (extent of PRMfSAD
and percent lung abnormality) using the mixed- effect
models described above. In addition to the stratification
variables, all models will adjust for age, race/ethnicity,
BMI (or height and weight) and smoking status.
Subgroups
Following the model of prior population studies, we will
stratify recruitment to include an approximately equal
number of men and women. This design enables us to test
hypothesised risk factors separately in women and men.
We anticipate that 40% of our sample will be non- white
race and that 25% will be Hispanic/Latinx. Although we
are not adequately powered to test for race/ethnicity-
based interactions for most of our risk factors of interest,
we will do stratified analyses by race/ethnicity that can be
informative for describing whether the patterns of associ-
ation within subgroups are consistent with those observed
in the full population.
Secondary analyses
The analyses of continuous and binary secondary cross-
sectional outcomes will use the methods and modelling
techniques described for the primary outcomes. Models
will include adjustment for potential confounders, which
may vary depending on the outcome of interest.
In addition to the cross- sectional data collected at the
in- person visit, longitudinal data will be collected through
the remote contacts. Continuous and binary outcomes will
be modelled as described for the primary analyses with the
addition of random effects and fixed effects (if appropriate)
for time to account for repeated measurements within the
on July 6, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2021-053342 on 5 July 2021. Downloaded from

8ReyfmanPA, etal. BMJ Open 2021;11:e053342. doi:10.1136/bmjopen-2021-053342
Open access
same individual. Events will be evaluated in two ways. Time
to first event will be graphically explored using Kaplan- Meier
curves, and comparisons will be made using Cox propor-
tional hazards models for individual outcomes (eg, time to
hospitalisation). Event rates and comparisons for repeated
events (eg, rates of influenza vaccination) will be modelled
using negative binomial regression to account for overdis-
persion, and the model will include a random effect to
account for within- site correlation.24
Missing data
A variety of sensitivity analyses will be performed to deter-
mine the potential impact of missing data on our conclu-
sions. ‘Best’ and ‘worst’ case single imputation techniques
will be implemented to define the range of impact. In
addition, the effect size that would need to be observed
in the missing data in order to change inference will be
computed. For a more sophisticated approach, a variety
of tools including but not limited to multiple imputation
and inverse probability weighting will be used.25 26
Ethics and dissemination
Observational Study Monitoring Board (OSMB)
The NHLBI appointed an OSMB who will review the charter,
protocol and consent prior to the study initiation. Thereafter,
the OSMB will meet annually with the research study team to
review data regarding recruitment, data completeness, data
quality and safety with additional meetings as needed. The
OSMB will also review ancillary study proposals to evaluate
the impact on participant burden and safety and the ability
to achieve the ALA- LHC’s objectives.
Institutional review board
IRB approval was obtained through a single IRB (Johns
Hopkins Medicine). Participating study sites are expected
to cede approval to the single IRB as per current NIH
policy.
Dissemination of data and biospecimens
The ALA- ACRC DCC has developed and tested proce-
dures for deidentification of PHI that meet the deiden-
tification standard established by Section 164.514 of the
HIPAA Privacy Rule. Deidentified datasets will be depos-
ited to BioLINCC at scheduled milestones (eg, following
completion of the baseline exam by all participants).
Deidentified (coded) biospecimens collected in the study
that are not analysed may be made available to qualified
investigators along with a limited- use dataset in line with
OHRP guidelines with a material transfer agreement
and/or data- use agreement as applicable. The ALA- ACRC
steering committee will review and, in consultation with
LHC multiple principal investigator (mPI) team, approve
requests for the use of biospecimens. A similar model
will be used for sharing images. The ALA- ACRC DCC has
extensive experience in preparation of limited- use data-
sets and maintains policies and model agreements for
data- use agreements and material transfer agreements.
Author afliations
1Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of
Medicine, Chicago, Illinois, USA
2Epidemiology, Johns Hopkins University Bloomberg School of Public Health,
Baltimore, Maryland, USA
3Department of Epidemiology, Johns Hopkins University Bloomberg School of Public
Health, Baltimore, Maryland, USA
4Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
5Pulmonary, Allergy and Critical Care Medicine, University of Alabama at
Birmingham, Birmingham, Alabama, USA
6Pulmonary and Critical Care Medicine, University of Michigan Michigan Medicine,
Ann Arbor, Michigan, USA
7Radiology, Brigham and Women's Hospital, Boston, Massachusetts, USA
8Harvard Medical School, Boston, Massachusetts, USA
9Division of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess
Medical Center, Boston, Massachusetts, USA
10Environmental Health, Harvard University T H Chan School of Public Health,
Boston, Massachusetts, USA
11Pulmonary and Critical Care, Brigham and Women's Hospital, Boston,
Massachusetts, USA
12Preventive Medicine, Northwestern University Feinberg School of Medicine,
Chicago, Illinois, USA
Acknowledgements American Lung Association Airways Clinical Research
Centers, Baylor College of Medicine, Houston: Nicola Hanania, MD (principal
investigator); David Wu, MD (coinvestigator); Dharani Narendra, MD (coinvestigator);
Thomas Monaco, MD (coinvestigator); Mariana Sockrider, MD (coinvestigator);
Mustafa Atik, MD (coordinator); Laura Bertrand, MD (coordinator). Brigham and
Women’s Hospital Asthma Research Center, Boston: Elliot Israel, MD (principal
investigator); Victoria Forth, NP (coinvestigator); Angeles Cinelli, BA (coordinator).
Columbia University Medical Center, New York: Emily DiMango, MD (principal
investigator); Tarnjot Saroya (coordinator). Cornell University, New York: Robert J.
Kaner, MD (principal investigator); Fernando J. Martinez, MD and MS
(coinvestigator); Jamuna Krishnan, MD and MBA (coinvestigator); William Z. Zhang,
MD (coinvestigator); Alicia J. Morris (coordinator); Lianne De La Cruz (coordinator);
Keyla Ordonez (coordinator); Elizabeth Peters, RN and BSN (admin contact). Duke
University Medical Center, Durham: Loretta G. Que, MD (principal investigator);
Jason Lang, MD (principal investigator); Anne Mathews, MD (coinvestigator);
Isaretta Riley, MD (coinvestigator); Antoinette M. Santoro, RRT (coordinator);
Catherine Foss, RRT (coordinator). Johns Hopkins University, Baltimore: Nadia
Hansel, MD/MPH (principal investigator); Ashraf Fawzy, MD (coinvestigator); Robert
Wise, MD (coinvestigator); Meredith McCormack, MD/MHS (coinvestigator);
Nirupama Putcha, MD/MHS (coinvestigator); Molly Lauver (coordinator); Karina
Romero Rivero, MD (coordinator). Medical University of South Carolina, Charleston:
Charlie Strange, MD (principal investigator); Margaret Hay, MD (coinvestigator);
Danielle Woodford (coordinator); Kristen Neff (coordinator). Mount Sinai National
Jewish Health Respiratory Institute, New York: Linda Rogers, MD (principal
investigator); Sonali Bose, MD (coinvestigator); Chelsea Chung (coordinator).
National Jewish Health Mount Sinai Respiratory Institute, Denver: Barry Make, MD
(principal investigator); Juno Pak (lead coordinator). Nemours Children's Health,
Jacksonville: Kathryn Blake, PharmD (principal investigator); Michelle Littleeld,
BSN and RN (coordinator). New York Medical College, New York: Allen J. Dozor, MD,
FCCP and FAAP (principal investigator); Alison T. Lennox, MD (principal investigator);
Zachary Messer (coordinator). New York University, New York: Joan Reibman, MD
(principal investigator); Rebecca Florsheim, MD (coinvestigator); Gail Schattner, MD
(coinvestigator); Brittany Marti (coordinator); Tsering Tenzing, NP (coordinator).
Northwestern University Feinberg School of Medicine, Chicago: Ravi Kalhan
(principal investigator), Sharon Rosenberg (coinvestigator), Paul Reyfman
(coinvestigator), Mercedes Carnethon (coinvestigator), Jenny Hixon (coordinator),
Vanessa Garcia (coordinator). Ohio State University, Columbus: Philip Diaz, MD
(principal investigator); Janice Drake (coordinator). Presbyterian Brooklyn Methodist
Hospital, Brooklyn: Jeremy Weingarten, MD, MBA and MS (principal investigator);
Christina Edwards, BS (coordinator). Rush University Medical Center, Chicago:
James Moy, MD (principal investigator); Ben Hu (coordinator); Jun Fu (coordinator).
St Vincent Health System, Indianapolis: Michael Busk, MD and MPH (principal
investigator); Ellen Looney (coordinator). Temple University Health System Lung
Center, Philadelphia: Gerard Criner, MD (principal investigator); Francine McGonagle
(coordinator); Antoinette Santoro (coordinator). University of Alabama at Birmingham
Lung Health Center, Birmingham: Mark Dranseld (principal investigator), Mike
Wells (coinvestigator), Surya Bhatt (coinvestigator), Trisha Parekh (coinvestigator),
Necole Seabron (coordinator), Renita Holmes (coordinator), Elizabeth Westfall
on July 6, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2021-053342 on 5 July 2021. Downloaded from

9
ReyfmanPA, etal. BMJ Open 2021;11:e053342. doi:10.1136/bmjopen-2021-053342
Open access
(centre director). University of Arizona, Tucson: Lynn B. Gerald, PhD and MSPH
(principal investigator); Dr Monica Kraft, MD (principal investigator); Chelsey Large,
CRC (coordinator); Michele Simon, CRC (coordinator); Raymond Skeps, MS
(coordinator). University of California, Los Angeles: Igor Barjaktarevic (principal
investigator), Donald P Tashkin (coinvestigator), Russell Buhr (coinvestigator),
Roslynn McGill (coordinator), Brian Jung (coordinator). University of California, San
Francisco: Stephen C. Lazarus, MD (principal investigator); Julian Silva, MA
(coordinator). University of Chicago Asthma and COPD Center, Chicago: Edward T.
Naureckas, MD (principal investigator); Virginia Zagaja (coordinator). University of
Colorado Anschutz Medical Campus, Aurora: Richard William Vandivier, MD
(principal investigator); Fernando Holguin, MD and MPH (coinvestigator); Margaret
Hope Cruse (coordinator); Vong Smith (asthma manager); Nancy Perez (coordinator);
Kisori Thomas (coordinator); Leah Freid (coordinator); Fernando Diaz del Valle
(coordinator). University of Florida, Jacksonville: James Cury (principal investigator),
Vandana Seeram (coinvestigator), Fallon Wainwright (coordinator). University of
Illinois Breathe Chicago Center, Chicago: Jerry A. Krishnan, MD and PhD (principal
investigator); Lauren Castro (coordinator); Julie DeLisa (coordinator); Wendy Haas
(coordinator); Jissell Torres (coordinator); Cindy Leman (director of admin
operations); Namrita Berry (grants/contracts); Jennifer Sculley (design strategist).
University of Iowa, Iowa City: Alejandro P Comellas (principal investigator), Kimberly
Sprenger (coordinator), Eric Garcia (coordinator), Deborah O'Connell- Moore.
University of Kansas Medical Center, Kansas City: Mario Castro, MD (principal
investigator); Chase Hall, MD (coinvestigator); Scott Matson, MD (coinvestigator);
Pam Kemp, PhD (coordinator); Vanessa Curtis, RRT (coordinator); Brynne Thompson,
RN (coordinator); Jonathan Boomer, PhD (laboratory/biospecimen planning and
processing); Josie Emery, BS (laboratory/biospecimen planning and processing);
Elaine Worth, BS (laboratory/biospecimen planning and processing). University of
Michigan, Ann Arbor: MeiLan Han, MD/MS (principal investigator); Alan Baptist, MD
(coinvestigator); Wassim Labaki, MD (coinvestigator); Craig Galban, PhD
(coinvestigator); Mary Kay Hamby (coordinator); Gretchen Bautista (project
manager). University of North Carolina Hospital Obstructive Lung Diseases Clinical
and Translational Research Center, Chapel Hill: M. Bradley Drummond, MD/MHS
(principal investigator); Karen Hardy (coordinator); Andrea McDaniel- Harper
(coordinator). University of Pittsburgh Emphysema/COPD Research Center,
Pittsburgh: Frank C. Sciurba, MD and FCCP (principal investigator); Elizabeth
Stempkowski, BA and CCRC (coordinator). University of Rochester Medical Center,
Rochester: Sandhya Khurana, MD (principal investigator); Jessica Newcomb
(research coordinator). University of Vermont Lung Center, Colchester: Charles Irvin,
PhD (principal investigator); Anne Dixon, MA/BM/BCh (coinvestigator); Kevin
Hodgdon RRT (coordinator). Pacic Northwest VA Puget Sound Health Care System,
Seattle: Laura Feemster (principal investigator), David Au (coinvestigator), Emily
Gleason (coordinator), Ed Udris (coordinator). University of Wisconsin Asthma,
Allergy, and Pulmonary Research, Madison: Loren C. Denlinger, MD and PhD
(principal investigator); Sean B. Fain, PhD (coinvestigator); Mark L. Schiebler, MD
(coinvestigator); Lori Wollet, RN (coordinator); Mary Jo Jackson, RN (coordinator);
Heather Floerke, BS (research specialist). Vanderbilt University Medical Center,
Nashville: Katherine Cahill, MD (principal investigator); Leonard Bacharier, MD
(coinvestigator); Julie Madison, RN (coordinator). Wake Forest Airways Clinical
Research Center, Winston- Salem: Wendy C. Moore, MD (principal investigator); Anna
Pippins, BS (coordinator); Isaac Deaton, BA, MA and EdS (coordinator). Chairman’s
Ofce University of Alabama, Birmingham: William C. Bailey, MD (chairman). LHC
Protocol Committee: Ravi Kalhan (chair, contact PI) and Sonali Bose, Deb Brown and
Mercedes R Carnethon, Mark T Dranseld, Laura Feemster, MeiLan Han, Heather
Hazucha, Janet Holbrook, Marc Lenburg, Carly Petrusky, Lisa Postow, Susan
Rappaport, Curt Reynolds, Mary Rice, Albert Rizzo, Alexandra Sierra, Elizabeth A
Sugar, Lisa Viviano, George R Washko Jr, Robert A Wise. Administrative Core,
Northwestern University: Ravi Kalhan (principal investigator), Mercedes Carnethon
(coinvestigator), Jenny Hixon. Data Coordinating Center, Johns Hopkins University
Center for Clinical Trials, Baltimore: Elizabeth A Sugar (principal investigator), Janet
Holbrook (coinvestigator), Robert Wise (coinvestigator), Curt Reynolds (lead
coordinator), Anne Casper (coordinator), Kathy Ewing (coordinator), Heather
Hazucha (coordinator), Alexis Rea (coordinator), Gem Roy (coordinator), Emily
Szilagyi (coordinator), Dave Shade (data system operator), Andie Lears (analyst), Jill
Meinert (analyst), Marie Daniel (spirometry quality control expert). Imaging Core,
Brigham and Women’s Hospital, Boston: George Washko (principal investigator),
Raul San Jose Estepar (coinvestigator), Pietro Nardelli (coinvestigator), Gonzalo
Vegas Sanchez- Ferrero (coinvestigator), James Ross (coinvestigator), Samuel Ash
(coinvestigator), Carrie Pistenmaa (coinvestigator), Stefanie Mason (coinvestigator),
Alejandro Diaz (coinvestigator), Monica Iturrioz, Ruben San Jose Estepar. Spirometry
Reading Center, Johns Hopkins University, Baltimore: Robert Wise (principal
investigator), Marie Daniel (coinvestigator). ALA ACRC Biorepository, Nemours
Children's Health, Jacksonville: Kathryn Blake (principal investigator), Ed Mougey
(coinvestigator). Environmental Exposures Core, Beth Israel Deaconess Medical
Center, Boston: Mary Rice (principal investigator), Murray Mittleman (coinvestigator).
Project Ofce, American Lung Association, New York: Alexandra Sierra, MA; Susan
Rappaport, MPH. Project Ofce, National Heart Lung and Blood Institute, Division of
Lung Diseases, Washington DC: Tom Croxton (branch chief, airways biology and
disease branch), Lisa Postow (program director, airway biology and disease branch),
Lisa Viviano (clinical trials specialist, ofce of the director). Observational Data
Safety Monitoring Board: Frank Gilliland (chair), Jonathan Goldin, Sharon Rounds,
Mario Sims, Daniela Sotres- Alvarez.
Collaborators Elliot Israel; Emily Dimango; Robert J. Kaner; Loretta G. Que;
Jason Lang; Nadia Hansel; Charlie Strange; Linda Rogers; Barry Make; Kathryn
Blake; Allan J. Dozor; Joan Reibman; Philip Diaz; Jeremy Weingarten; James Moy;
Michael Busk; Gerard Criner; Lynn B. Gerald; Monica Kraft; Igor Barjaktarevic;
Stephen C. Lazarus; Edward T. Naureckas; Richard W. Vandivier; James Cury;
Jerry A. Krishnan; Alejandro P. Comellas; Mario Castro; M. Bradley Drummond;
Frank C. Sciurba; Sandhya Khurana; Charles Irvin; Laura Feemster; Loren C.
Denlinger; Katherine Cahill; Wendy C. Moore; William C. Bailey; Janet Holbrook;
Robert A. Wise; Murray Mittleman; Alexandra Sierra; Susan Rappaport; Albert
Rizzo.
Contributors ES, MTD, MKH, RSJE, MBR, GRW, MC and RK contributed to the
conception and design of the study. HH, JH, CR, SB, RSJE, MBR, GRW, ES, MC and
RK developed the study protocol. PAR, ES and RK wrote the manuscript with input
from all other authors.
Funding This work was supported by the National Heart, Lung, and Blood Institute
grant number U01HL146408 and the American Lung Association.
Competing interests PAR reports personal fees from Medscape and Guidepoint,
outside the submitted work. MTD reports personal fees and participation in
contracted clinical trials from Boehringer Ingelheim, GlaxoSmithKline and
AstraZeneca, outside the submitted work; participation in contracted clinical trials
from Yungjin, PneumRx/BTG, Gala and Nuvaira, outside the submitted work; non-
nancial support, travel support and participation in contracted clinical trials from
Pulmonx, outside the submitted work; personal fees from Quark Pharmaceuticals,
Mereo, Teva and CSA Medical, outside the submitted work; and grants from ALA,
outside the submitted work. MKH reports personal fees from PrimeInc, during
the conduct of the study; personal fees from AstraZeneca, Boehringer Ingelheim,
GlaxoSmithKline, Cipla, Chiesi, Teva, Verona, Merck, Mylan and Sano, outside the
submitted work; and research support from Novartis and Sunovion, outside the
submitted work. RSJE is a founder and co- owner of Quantitative Imaging Solutions,
outside the submitted work, and reports research support from Insmed and Lung
Biotechnology, outside the submitted work; research support and personal fees
from Boehringer Ingelheim, outside the submitted work; and personal fees from
Chiesi and LeukoLabs, outside the submitted work. GRW is a founder and co- owner
of Quantitative Imaging Solutions, outside the submitted work, and reports personal
fees, research support and advisory board participation from Boehringer Ingelheim,
outside the submitted work; personal fees and chairing of DSMB from PulmonX,
outside the submitted work; personal fees and research support from Janssen
Pharmaceuticals, outside the submitted work; personal fees from Novartis, outside
the submitted work; and personal fees and advisory board participation from
Vertex and CSL Behring, outside the submitted work, and GRW’s spouse works for
Biogen. RK reports research support from PneumRx (BTG) and Spiration, outside
the submitted work; personal fees and research support from AstraZeneca and
GlaxoSmithKline, outside the submitted work; and personal fees from Boehringer
Ingelheim, CVS Caremark, Boston Scientic and Boston Consulting Group, outside
the submitted work.
Patient and public involvement Patients and/or the public were not involved in
the design, conduct, reporting or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; peer reviewed for ethical and
funding approval prior to submission.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY- NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non- commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non- commercial. See:http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.
ORCID iDs
Paul AReyfman http:// orcid. org/ 0000- 0002- 6435- 6001
RaviKalhan http:// orcid. org/ 0000- 0003- 2443- 0876
on July 6, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2021-053342 on 5 July 2021. Downloaded from

10 ReyfmanPA, etal. BMJ Open 2021;11:e053342. doi:10.1136/bmjopen-2021-053342
Open access
REFERENCES
1 Reyfman PA, Washko GR, Dranseld MT, etal. Dening impaired
respiratory health. A paradigm shift for pulmonary medicine. Am J
Respir Crit Care Med 2018;198:440–6.
2 National Heart, Lung, and Blood Institute, National Institutes
of Health, Department of Health and Human Services. New
epidemiology cohort studies in heart, lung, blood, and sleep
diseases and disorders (u01 - clinical trial not allowed), 2018.
Available: https:// grants. nih. gov/ grants/ guide/ pa- les/ PAR- 18- 577.
htm
3 Miller MR, Hankinson J, Brusasco V, etal. Standardisation of
spirometry. Eur Respir J 2005;26:319–38.
4 Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference
values from a sample of the general U.S. population. Am J Respir
Crit Care Med 1999;159:179–87.
5 Fedorov A, Beichel R, Kalpathy- Cramer J, etal. 3D slicer as an image
computing platform for the quantitative imaging network. Magn
Reson Imaging 2012;30:1323–41.
6 Cheng TL, Goodman E. Committee on pediatric R. race, ethnicity,
and socioeconomic status in research on child health. Pediatrics
2015;135:e225–37.
7 Polak M, Szafraniec K, Kozela M, etal. Socioeconomic status and
pulmonary function, transition from childhood to adulthood: cross-
sectional results from the Polish part of the HAPIEE study. BMJ Open
2019;9:e022638.
8 Di Q, Dominici F, Schwartz JD. Air pollution and mortality in the
Medicare population. N Engl J Med 2017;377:2513–22.
9 Di Q, Rowland S, Koutrakis P, etal. A hybrid model for spatially
and temporally resolved ozone exposures in the continental United
States. J Air Waste Manag Assoc 2017;67:39–52.
10 Kloog I, Chudnovsky AA, Just AC, etal. A new hybrid spatio-
temporal model for estimating daily multi- year PM2.5 concentrations
across northeastern USA using high resolution aerosol optical depth
data. Atmos Environ 2014;95:581–90.
11 Ash SY, Harmouche R, Ross JC, etal. The objective identication
and quantication of interstitial lung abnormalities in smokers. Acad
Radiol 2017;24:941–6.
12 Ash SY, Harmouche R, Ross JC, etal. Interstitial features at chest
CT enhance the deleterious effects of emphysema in the COPDGene
cohort. Radiology 2018;288:600–9.
13 Ash SY, Harmouche R, Vallejo DLL, etal. Densitometric and local
histogram based analysis of computed tomography images
in patients with idiopathic pulmonary fibrosis. Respir Res
2017;18:45.
14 Bhatt SP, Soler X, Wang X, etal. Association between
functional small airway disease and FEV1 decline in chronic
obstructive pulmonary disease. Am J Respir Crit Care Med
2016;194:178–84.
15 Galbán CJ, Han MK, Boes JL, etal. Computed tomography–based
biomarker provides unique signature for diagnosis of COPD
phenotypes and disease progression. Nat Med 2012;18:1711–5.
16 Kalhan R, Dranseld MT, Colangelo LA, etal. Respiratory symptoms
in young adults and future lung disease. The cardia lung study. Am J
Respir Crit Care Med 2018;197:1616–24.
17 Harris PA, Taylor R, Minor BL, etal. The REDCap Consortium:
building an international community of software platform partners. J
Biomed Inform 2019;95:103208.
18 Harris PA, Taylor R, Thielke R, etal. Research electronic data capture
(REDCap)—A metadata- driven methodology and workow process
for providing translational research informatics support. J Biomed
Inform 2009;42:377–81.
19 Kalhan R, Arynchyn A, Colangelo LA, etal. Lung function in young
adults predicts airow obstruction 20 years later. Am J Med
2010;123:468.e1–468.e7.
20 Smith LJ, Kalhan R, Wise RA, etal. Effect of a soy isoavone
supplement on lung function and clinical outcomes in patients with
poorly controlled asthma. JAMA 2015;313:2033–43.
21 American Lung Association Asthma Clinical Research Centers,
Peters SP, Anthonisen N, etal. Randomized comparison of strategies
for reducing treatment in mild persistent asthma. N Engl J Med
2007;356:2027–39.
22 Sin DD, Wu L, Man SFP. The relationship between reduced lung
function and cardiovascular mortality: a population- based study and
a systematic review of the literature. Chest 2005;127:1952–9.
23 Kalhan R, Dranseld MT, Colangelo LA, etal. Respiratory symptoms
in young adults and future lung disease. The cardia lung study. Am J
Respir Crit Care Med 2018;197:1616–24.
24 Keene ON, Jones MRK, Lane PW, etal. Analysis of exacerbation
rates in asthma and chronic obstructive pulmonary disease: example
from the TRISTAN study. Pharm Stat 2007;6:89–97.
25 Daniels MH JW. Missing data in longitudinal studies; strategies for
Bayesian modeling and sensitivity analysis. Boca Raton: Chapman &
Hall/CRC Press, 2008.
26 Little RJA, Rubin DB. Statistical analysis with missing data. 2nd ed.
Hoboken, N.J: Wiley, 2002.
27 Global Initiative for Asthma. Global strategy for asthma management
and prevention, 2021. Available: www. ginasthma. org
28 Togias A, Gergen PJ, Hu JW, etal. Rhinitis in children and
adolescents with asthma: ubiquitous, difcult to control, and
associated with asthma outcomes. J Allergy Clin Immunol
2019;143:1003–11.
29 Chu AHY, Ng SHX, Koh D, etal. Reliability and validity of the self-
and Interviewer- Administered versions of the global physical activity
questionnaire (GPAQ). PLoS One 2015;10:e0136944.
30 Buysse DJ, Reynolds CF, Monk TH, etal. The Pittsburgh sleep
quality index: a new instrument for psychiatric practice and research.
Psychiatry Res 1989;28:193–213.
on July 6, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2021-053342 on 5 July 2021. Downloaded from