The Families-At-risk for Interstitial Lung Disease Study
Conditions: Interstitial Lung Disease, Idiopathic Pulmonary Fibrosis
Sponsor: Columbia University

Families At-Risk for Interstitial Lung Disease Study 
NCT number: NCT03641742 
Document Date: 9/1/2023 
Published Manuscript reporting Results: McGroder et al Chest 2023 (PMID 36649755) 
 
Study Protocol and Statistical Analysis: 
Participants 
The institutional review board at Columbia University Irving Medical Center approved 
this study (AAAR1916). Written informed consent was obtained from all participants. We 
enrolled asymptomatic first-degree relatives, hereafter referred to as at-risk participants (ARPs), 
of patients clinically diagnosed with any number of fibrotic lung diseases, including IPF, CHP, 
CTD-ILD, pleuroparenchymal fibroelastosis (PPFE) and unclassifiable fibrotic ILD. At-risk 
participants were at least 35 years old and were excluded if they had underlying lung disease, a 
history of chronic heart failure, liver or kidney disease, a history of drug use during the last year, 
or if they were pregnant. Each ARP was interviewed by research personnel and detailed family 
pedigrees were created. If the affected individual’s pedigree contained at least two family 
members with pulmonary fibrosis, they were deemed a familial case. Sporadic cases included 
those with no known family history of a fibrotic ILD.  Affected probands with Interstitial Lung 
Disease, that is, those who were related to the ARPs, were enrolled if alive and available to 
participate in the study. 
Testing 
Each ARP underwent a high-resolution computed tomography (HRCT) scan of the chest 
at full inspiration using a single GE 64 VCT machine. The presence of a preclinical ILA, defined 
as non-dependent ground-glass abnormalities, reticulations, non-emphysematous cysts, traction 
bronchiectasis or honeycombing affecting > 5% of any lung zone1, was determined by 
consensus of two thoracic radiologists. Focal findings or patterns taking up less than 5% of a 

lung zone were deemed “indeterminate” for ILA and disregarded. If architectural distortion with 
bilateral fibrosis was present, the radiologists categorized the HRCT pattern per the American 
Thoracic Society criteria (usual interstitial pneumonia (UIP) pattern, probable UIP pattern, 
indeterminate for UIP, or suggestive of alternate diagnosis)2. 
We obtained a quantitative assessment of lung attenuation using the Pulmonary 
Analysis Software Suite3,4. High attenuation areas (HAA) were defined as percentage of the 
lung with attenuation between -600 and -250 HU as previously described5.  
Spirometry was performed in accordance with American Thoracic Society/European 
Respiratory Society guidelines. ARPs completed a 6-minute walk tests and the cough visual 
analog score.  
We obtained genomic DNA from blood leukocytes using the Gentra Puregene Blood kit 
(Qiagen, Valencia CA). Blood leukocyte telomere length (LTL) was measured using a 
quantitative PCR assay6. Age-adjusted LTL percentiles were calculated after comparison with 
normal controls. Genotyping for the MUC5B (rs35705950) risk allele was obtained by Sanger 
sequencing and the minor allele frequency was calculated.  
Statistical Analysis  
We compared clinical characteristics of ARPs with and without ILA/ILD using chi-
squared tests, Fisher’s exact tests, and Wilcoxon rank sum tests, where appropriate. We used 
generalized linear models to account for family clustering. Within these models, we included the 
variable of interest in addition to a random intercept for household number to account for the 
hierarchical nature of the data.       
 
 
 

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