Kevin K Brown

National Jewish Health, Denver, Colorado, United States

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Publications (226)1524.44 Total impact

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    ABSTRACT: Idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous, somewhat unpredictable diseases characterized by progressive scarring of the interstitium. Since lung function is a key determinant of survival, we reasoned that the transcriptional profile in IIP lung tissue would be associated with measures of lung function, and could enhance prognostic approaches to IIPs. Using gene expression profiling of 167 lung tissue specimens with IIP diagnosis and 50 control lungs, we identified genes whose expression is associated with changes in lung function (% predicted FVC and % predicted D L CO) modeled as categorical (severe vs mild disease) or continuous variables while adjusting for smoking status and IIP subtype; false discovery rate (FDR) approach was used to correct for multiple comparisons. This analysis identified 58 transcripts that are associated with mild vs severe disease (categorical analysis), including those with established role in fibrosis (ADAMTS4, ADAMTS9, AGER, HIF-1α, SERPINA3, SERPINE2, and SELE) as well as novel IIP candidate genes such as rhotekin 2 (RTKN2) and peptidase inhibitor 15 (PI15). Protein-protein interactome analysis of 553 genes whose expression is significantly associated with lung function when modeled as continuous variables demonstrates that more severe presentation of IIPs is characterized by an increase in cell cycle progression and apoptosis, increased hypoxia, and dampened innate immune response. Our findings were validated in an independent cohort of 131 IIPs and 40 controls at the mRNA level and for one gene (RTKN2) at the protein level by immunohistochemistry in a subset of samples. We identified commonalities and differences in gene expression among different subtypes of IIPs. Disease progression, as characterized by lower measures of FVC and D L CO, results in marked changes in expression of novel and established genes and pathways involved in IIPs. These genes and pathways represent strong candidates for biomarker studies and potential therapeutic targets for IIP severity.
    BMC Genomics 12/2015; 16(1). DOI:10.1186/s12864-015-2102-3 · 3.99 Impact Factor
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    ABSTRACT: Interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis. There is lack of clarity around predictors of mortality and disease behaviour over time in these patients.We identified rheumatoid arthritis-related interstitial lung disease (RA-ILD) patients evaluated at National Jewish Health (Denver, CO, USA) from 1995 to 2013 whose baseline high-resolution computed tomography (HRCT) scans showed either a nonspecific interstitial pneumonia (NSIP) or a "definite" or "possible" usual interstitial pneumonia (UIP) pattern. We used univariate, multivariate and longitudinal analytical methods to identify clinical predictors of mortality and to model disease behaviour over time.The cohort included 137 subjects; 108 had UIP on HRCT (RA-UIP) and 29 had NSIP on HRCT (RA-NSIP). Those with RA-UIP had a shorter survival time than those with RA-NSIP (log rank p=0.02). In a model controlling for age, sex, smoking and HRCT pattern, a lower baseline % predicted forced vital capacity (FVC % pred) (HR=1.46; p<0.0001) and a 10% decline in FVC % pred from baseline to any time during follow up (HR=2.57; p<0.0001) were independently associated with an increased risk of death.Data from this study suggest that in RA-ILD, disease progression and survival differ between subgroups defined by HRCT pattern; however, when controlling for potentially influential variables, pulmonary physiology, but not HRCT pattern, independently predicts mortality.
    European Respiratory Journal 11/2015; DOI:10.1183/13993003.00357-2015 · 7.64 Impact Factor
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    ABSTRACT: The objective of this study was to determine the safety and efficacy of carlumab in the treatment of idiopathic pulmonary fibrosis (IPF).A phase 2, randomised, double-blind placebo-controlled dose-ranging study was conducted in patients with IPF (n=126). Patients were randomised to carlumab (1 mg·kg(-1), 5 mg·kg(-1), or 15 mg·kg(-1)) or placebo every 4 weeks. The primary endpoint was the rate of percentage change in forced vital capacity (FVC). Secondary endpoints were time to disease progression, absolute change in FVC, relative change in diffusing capacity of the lung for carbon monoxide (DLCO), and St George's Respiratory Questionnaire (SGRQ) total score.Due to a pre-planned, unfavourable interim benefit-risk analysis, dosing was suspended. The rate of percentage change in FVC showed no treatment effect (placebo -0.582%, 1 mg·kg(-1) -0.533%, 5 mg·kg(-1) -0.799% and 15 mg·kg(-1) -0.470%; p=0.261). All active treatment groups showed a greater decline in FVC (1 mg·kg(-1) -290 mL, 5 mg·kg(-1) -370 mL and 15 mg·kg(-1) -320 mL) compared with placebo (-130 mL). No effect on disease progression, DLCO, infection rates or mortality was observed. SGRQ scores showed a nonsignificant trend toward worsening with active treatment. Unexpectedly, free CC-chemokine ligand 2 levels were elevated above baseline at both 24 and 52 weeks. A higher proportion of patients with one or more serious adverse events was observed in the 5 mg·kg(-1) group (53.1%) compared with 1 mg·kg(-1) (15.2%), 15 mg·kg(-1) (21.9%) and placebo (46.4%), although no unexpected serious adverse events were noted.Although dosing was stopped prematurely, it is unlikely that carlumab provides benefit to IPF patients.
    European Respiratory Journal 10/2015; DOI:10.1183/13993003.01558-2014 · 7.64 Impact Factor
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    ABSTRACT: Background: Idiopathic pulmonary fibrosis is a progressive lung disease with variable course in individuals. The Gender-Age-Physiology (GAP) Index stage uses clinical variables to stage mortality risk. It is unknown whether clinical staging predicts future pulmonary function decline. We assess whether the GAP stage predicts future pulmonary function decline, and whether interval pulmonary function change predicts mortality after accounting for stage. Methods: Patients with Idiopathic Pulmonary Fibrosis (n=657) were identified retrospectively at three tertiary referral centers and baseline GAP stage assessed. Mixed models describe average trajectories of forced vital capacity (FVC) and diffusion capacity (DLCO). Multivariable Cox proportional hazards models assess whether pulmonary function declines of 10% or more in 6 months predict mortality after accounting for stage. Results: Over 2 years, GAP stage was not associated with differences in yearly lung function decline. After accounting for stage, a 10% decrease in FVC or DLCO over 6 months independently predicted death or transplant (FVC HR=1.37, DLCO HR 1.30, both p≤0.03). GAP stage 2 patients with declining pulmonary function experienced a survival profile similar to GAP 3 patients with 1-year event-free survival of 59.3% (CI95% 49.4-67.8) versus 56.9% (CI95% 42.2-69.1). Conclusions: Baseline GAP stage predicts death or lung transplantation, but not the rate of future pulmonary function decline. After accounting for GAP stage, a decline of 10% or more over 6 months independently predicts death or lung transplant.
    Chest 10/2015; DOI:10.1378/chest.15-0530 · 7.48 Impact Factor
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    ABSTRACT: The clinical course of pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) is not known except in advanced disease.488 subjects in a placebo-controlled study of ambrisentan in IPF with mild-moderate restriction in lung volume, underwent right heart catheterisation (RHC) at baseline and 117 subjects (24%) had repeated haemodynamic measurements at 48 weeks.The subjects were categorised into a) World Health Organization (WHO) Group 3 PH (PH associated with pulmonary disease), n=68 (14%); b) WHO Group 2 PH (PH associated with left-sided cardiac disease), n=25 (5%); c) no PH but elevated pulmonary artery wedge pressure (PAWP), n=21 (4%); and d) no PH but without elevation of PAWP, n=374 (77%). The WHO Group 3 PH subjects had a lower diffusion capacity, 6MWD and oxygen saturation compared to the subjects with no PH. There was no significant change in mean pulmonary arterial pressure with ambrisenten or placebo after 12 months.Subjects with IPF associated with WHO Group 3 PH had impaired gas exchange and exercise capacity compared to patients without PH. An additional 9% of the subjects had haemodynamic evidence of subclinical left-ventricular dysfunction. Pulmonary artery pressures remained stable over 1 year in the majority of the cohort. Copyright ©ERS 2015.
    European Respiratory Journal 08/2015; 46(5). DOI:10.1183/13993003.01537-2014 · 7.64 Impact Factor
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    ABSTRACT: The goal of this review is to summarise the clinical features, management, and prognosis of acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF). AE-IPF has previously been defined based on clinical and radiological features that include the subacute onset of dyspnoea, bilateral ground glass changes on chest high-resolution computed tomography, and the absence of an identifiable aetiology. The annual incidence of AE-IPF is typically reported at 5-15%, but is less common in mild disease. Features of diffuse alveolar damage are present when a biopsy is performed. Idiopathic pulmonary fibrosis (IPF) patients with acute respiratory worsening are often initially treated with high dose corticosteroids and antimicrobials; however, there are no clear data to support these therapies, and the short-term mortality of AE-IPF is ∼50%. Recent studies have shown that the features and prognosis of AE-IPF are similar to other causes of acute respiratory worsening, including infection, aspiration, air pollution and mechanical injury to the alveolar epithelium. Based on this emerging evidence, we propose a novel approach to the classification of acute respiratory worsening events in patients with IPF that focuses on clinical and radiological findings consistent with an underlying pathobiology of diffuse alveolar damage. Copyright ©ERS 2015.
    European Respiratory Journal 08/2015; 46(2):512-520. DOI:10.1183/13993003.00419-2015 · 7.64 Impact Factor
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    ABSTRACT: Many patients with an idiopathic interstitial pneumonia (IIP) have clinical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease (CTD). Researchers have proposed differing criteria and terms to describe these patients, and lack of consensus over nomenclature and classification limits the ability to conduct prospective studies of a uniform cohort.The "European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease" was formed to create consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity.The task force proposes the term "interstitial pneumonia with autoimmune features" (IPAF) and offers classification criteria organised around the presence of a combination of features from three domains: a clinical domain consisting of specific extra-thoracic features, a serologic domain consisting of specific autoantibodies, and a morphologic domain consisting of specific chest imaging, histopathologic or pulmonary physiologic features.A designation of IPAF should be used to identify individuals with IIP and features suggestive of, but not definitive for, a CTD. With IPAF, a sound platform has been provided from which to launch the requisite future research investigations of a more uniform cohort. Copyright ©ERS 2015.
    European Respiratory Journal 07/2015; 46(4). DOI:10.1183/13993003.00150-2015 · 7.64 Impact Factor
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    ABSTRACT: Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease that distorts pulmonary architecture, leading to hypoxia, respiratory failure, and death. Diagnosis is difficult because other interstitial lung diseases have similar radiological and histopathological characteristics. A usual interstitial pneumonia pattern is a hallmark of idiopathic pulmonary fibrosis and is essential for its diagnosis. We aimed to develop a molecular test that distinguishes usual interstitial pneumonia from other interstitial lung diseases in surgical lung biopsy samples. The eventual goal of this research is to develop a method to diagnose idiopathic pulmonary fibrosis without the patient having to undergo surgery.
    05/2015; 3(6). DOI:10.1016/S2213-2600(15)00140-X
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    ABSTRACT: The response of the right ventricle (RV) to pulmonary arterial hypertension (PAH) involves changes in contractile function, chamber size, hypertrophy, and extracellular matrix (ECM). Galectin-3 (Gal-3) is a mediator of myocardial ECM metabolism and biomarker for left heart remodeling, yet its ability to reflect RV remodeling is unknown. We hypothesized that serum Gal-3 levels correlate with RV morphology and function in PAH, and that Gal-3 is associated with circulating markers of ECM. Fifteen subjects with PAH and 10 age-matched controls underwent same-day echocardiography, cardiac magnetic resonance (CMR) imaging, and phlebotomy for Gal-3 and ECM biomarkers including N-terminal propeptide of type III collagen type (PIIINP), tissue inhibitor of metalloproteinase-1 (TIMP-1), and hyaluronic acid (HA). RV ejection fraction, end diastolic volume index, end systolic volume index, and mass index were calculated using CMR. Echocardiography was used to estimate RV systolic pressure and measure RV strain. Serum Gal-3, TIMP-1, and HA levels were all significantly increased in PAH subjects when compared to controls. Gal-3 correlated with RV ejection fraction (ρ −0.44, p 0.03), end diastolic volume index (ρ 0.42, p 0.03), end systolic volume index (ρ 0.44, p 0.027), mass index (ρ 0.47, p 0.016), systolic pressure (ρ 0.55, p
    Heart and Vessels 05/2015; DOI:10.1007/s00380-015-0691-z · 2.07 Impact Factor
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    ABSTRACT: The past decade has seen substantial progress in understanding the pathobiology, natural history, and clinical significance of idiopathic pulmonary fibrosis (IPF), culminating in the establishment of two effective medical therapies. Now seems an important time to reconsider the design and conduct of future IPF clinical trials. Building on lessons learned over the past decade, we use this perspective to lay out four key considerations for moving forward effectively and efficiently with the next generation of clinical trials in IPF. These are: development of a coordinated IPF clinical trials network; establishment of expectations for early phase proof of concept studies; adaptation of late-phase efficacy trial designs to the emergence of approved therapies, and; agreement on primary end-points for late phase clinical trials. Continued progress in the field of IPF will require creativity and collaboration on the part of all stakeholders. We believe that addressing these four considerations will encourage and enable investment in this new era of drug development in IPF, and will lead to more rapid development of effective therapies. Copyright ©ERS 2015.
    European Respiratory Journal 04/2015; 46(1). DOI:10.1183/09031936.00200614 · 7.64 Impact Factor
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    ABSTRACT: Mortality is an impractical primary endpoint for clinical trials in patients with idiopathic pulmonary fibrosis who have mild-to-moderate physiological impairment because event rates are low. Change in forced vital capacity (FVC) is widely accepted as a surrogate for mortality and is the most common primary endpoint in clinical trials for this disorder. Use of hospital admission as a predictor for mortality, independent of FVC decline, has not been well defined. We aimed to ascertain the independent and combined association of hospital admission and at least a 10% decrease in FVC with all-cause mortality.
    04/2015; 3(5). DOI:10.1016/S2213-2600(15)00093-4
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    ABSTRACT: Physical functional capacity is impaired in idiopathic pulmonary fibrosis (IPF). There is no tool to measure this key clinical outcome. The continuous-scale physical function performance (CS-PFP) test is one that assesses activities of daily living, but it has never been used in IPF. We determined internal consistency of the CS-PFP. We used correlations to assess the strength of association between CS-PFP scores and various parameters of IPF severity, and compared the CS-PFP scores between patients with IPF and published values from a healthy control group. Sixteen subjects completed the test and retest. Test-retest reliability (0.84, p = 0.003) and internal consistency (Cronbach's α = 0.91) were excellent. Subjects with IPF had significantly worse CS-PFP scores than controls (46.0 ± 11.1 vs 58.7 ± 12.5, p = 0.001). In IPF, the CS-PFP scores correlated moderately to very strongly with several disease severity variables. The CS-PFP is a reliable and valid tool in IPF.
    Expert Review of Respiratory Medicine 04/2015; 9(3):1-7. DOI:10.1586/17476348.2015.1030396
  • Tristan J. Huie · Kevin K. Brown ·
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing interstitial lung disease of unknown etiology characterized by progressive lung scarring and a median survival of 3-5 years from the time of diagnosis. The most recent consensus guidelines adopt a diagnostic process that characterizes patients as having a final diagnosis of IPF, probable IPF, or possible IPF determined from a combination of the clinical context and specific chest imaging and histologic disease patterns. Based on currently available data, the enrollment criteria for treatment trials could be expanded to include not only patients with IPF but also those with probable and possible IPF without adversely affecting trial design or outcomes. Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
    03/2015; 53(3). DOI:10.1016/j.resinv.2014.12.005
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    ABSTRACT: Background: Up to 20% of cases of idiopathic interstitial pneumonia (IIP) cluster in families, comprising the syndrome of Familial Interstitial Pneumonia (FIP); however, the genetic basis of FIP remains uncertain in a majority of families. We hypothesized that new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis. Methods: Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing (WES) from genomic DNA. Candidate rare variants were confirmed by Sanger sequencing and co-segregation analysis was performed in families, followed by additional sequencing of affected individuals from another163 kindreds. Results: We identified a potentially damaging rare variant in the gene encoding for regulator of telomere elongation helicase 1 (RTEL1) that segregated with disease and was associated with very short telomeres in peripheral blood mononuclear cells in one of 25 families in our original WES cohort. Evaluation of affected individuals in 163 additional kindreds revealed another 8 families (5%) with heterozygous rare variants in RTEL1 that segregated with clinical FIP. Probands and unaffected carriers of these rare variants had short telomeres (<10% for age) in peripheral blood mononuclear cells and increased T-circle formation, suggesting impaired RTEL1 function. Conclusions: Rare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis.
    American Journal of Respiratory and Critical Care Medicine 02/2015; 21(6). DOI:10.1164/rccm.201408-1510OC · 13.00 Impact Factor
  • Aryeh Fischer · Kevin K Brown ·
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    ABSTRACT: The intersection of interstitial lung disease (ILD) and connective tissue disease (CTD) is complex and commonly includes the scenario whereby ILD is identified in patients with pre-existing CTD, is the presenting manifestation of an occult CTD, or arises within the context of a suggestive form of CTD. Determining that an ILD is CTD-associated is important because this knowledge often impacts management and prognosis. Identifying occult CTD in patients with presumed idiopathic ILD can be challenging and requires a comprehensive, often multidisciplinary, evaluation. There is much uncertainty and controversy surrounding the suggestive forms of CTD-associated ILD (CTD-ILD) and prospective studies are needed to provide a better understanding of the natural history of these cohorts, how to best manage them, and to determine whether they behave similar to classifiable forms of CTD-ILD. © 2014 American College of Rheumatology.
    01/2015; 67(1). DOI:10.1002/acr.22394
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    ABSTRACT: Background Peripheral blood biomarkers might improve diagnostic accuracy for idiopathic pulmonary fibrosis (IPF). Results Gene expression profiles were obtained from 89 patients with IPF and 26 normal controls. Samples were stratified according to severity of disease based on pulmonary function. The stratified dataset was split into subsets; two-thirds of the samples were selected to comprise the training set, while one-third was reserved for the validation set. Bayesian probit regression was used on the training set to develop a gene expression model for IPF versus normal. The gene expression model was tested by using it on the validation set to perform class prediction. Unsupervised clustering failed to discriminate between samples of different severity. Therefore, samples of all severities were included in the training and validation sets, in equal proportions. A gene signature model was developed from the training set. The model was built in an iterative fashion with the number of gene features selected to minimize the misclassification error in cross validation. The final model was based on the top 108 discriminating genes in the training set. The signature was successfully applied to the validation set, ROC area under the curve = 0.893, p < 0.0001. Using the optimal threshold (0.74) accurate class predictions were made for 77% of the test cases with sensitivity = 0.70, specificity = 1.00. Conclusions By using Bayesian probit regression to develop a model, we show that it is entirely possible to make a diagnosis of IPF from the peripheral blood with gene signatures. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-902) contains supplementary material, which is available to authorized users.
    BMC Genomics 10/2014; 15(1):902. DOI:10.1186/1471-2164-15-902 · 3.99 Impact Factor
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    ABSTRACT: Background: The current usual interstitial pneumonitis (UIP)/idiopathic pulmonary fibrosis CT scan classification system excludes probable UIP as a diagnostic category. We sought to determine the predictive effect of probable UIP on CT scan on histology and the effect of the promoter polymorphism in MUC5B (rs35705950) on histologic and CT scan UIP diagnosis. Methods: The cohort included 201 subjects with pulmonary fibrosis who had lung tissue samples obtained within 1 year of chest CT scan. UIP diagnosis on CT scan was categorized as inconsistent with, indeterminate, probable, or definite UIP by two to three pulmonary radiologists. Tissue slides were scored by two expert pulmonary pathologists. All subjects with available DNA (N = 200) were genotyped for rs35705950. Results: The proportion of CT scan diagnoses were as follows: inconsistent with (69 of 201, 34.3%), indeterminate (72 of 201, 35.8%), probable (34 of 201, 16.9%), and definite (26 of 201, 12.9%) UIP. Subjects with probable UIP on CT scan were more likely to have histologic probable/definite UIP than subjects with indeterminate UIP on CT scan (82.4% [28 of 34] vs 54.2% [39 of 72]; P = .01). CT scan and microscopic honeycombing were not associated with each other (P = .76). The minor (T) allele of the MUC5B polymorphism was associated with concordant CT scan and histologic UIP diagnosis (P = .03). Conclusions: Probable UIP on CT scan is associated with a higher rate of histologic UIP than indeterminate UIP on CT scan suggesting that they are distinct groups and should not be combined into a single CT scan category as currently recommended by guidelines. CT scan and microscopic honeycombing may be dissimilar entities. The T allele at rs35705950 predicts a UIP diagnosis by both chest CT scan and histology.
    Chest 10/2014; 147(2). DOI:10.1378/chest.14-0976 · 7.48 Impact Factor
  • Brett Ley · Kevin K Brown · Harold R Collard ·
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    ABSTRACT: Molecular biomarkers are highly desired in idiopathic pulmonary fibrosis (IPF) where they hold the potential to elucidate underlying disease mechanisms, accelerated drug development, and advance clinical management. Currently, there are no molecular biomarkers in widespread clinical use for IPF, and the search for potential markers remains in its infancy. Proposed core mechanisms in the pathogenesis of IPF for which candidate markers have been offered include alveolar epithelial cell dysfunction, immune dysregulation, and fibrogenesis. Useful markers reflect important pathologic pathways, are practically and accurately measured, have undergone extensive validation, and are an improvement upon the current approach for their intended use. The successful development of useful molecular biomarkers is a central challenge for the future of translational research in IPF and will require collaborative efforts among those parties invested in advancing the care of patients with IPF.
    AJP Lung Cellular and Molecular Physiology 09/2014; 307(9). DOI:10.1152/ajplung.00014.2014 · 4.08 Impact Factor
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    ABSTRACT: While widespread use of animal modeling has transformed pulmonary research, the overarching goal of biomedical research is to enhance our understanding of human physiology and pathology. Thus, we believe that future gains in understanding human lung disease will be enhanced when studying patient-derived samples becomes an integral part of the investigational process. For idiopathic pulmonary fibrosis (IPF), investigators need quality human specimens, collected in a standardized fashion, along with carefully annotated, long-term clinical and outcomes data to address current knowledge gaps. Access to human lung tissues through commercial entities or the Lung Tissue Resource Consortium, an NHLBI-funded consortium, has demonstrated the feasibility of this approach. However, these samples are not always well-annotated or collected uniformly, and are limited in their breadth to address future IPF research needs. Therefore, we propose leveraging ongoing and future studies in IPF to establish a biorepository which will meet current and future needs of IPF investigations. Specifically, we propose that blood, cell, and lung samples, linked to robust longitudinal clinical phenotyping generated from future industry, federally-sponsored, and investigator-initiated clinical studies be prospectively and uniformly collected and stored in a biorepository and linked registry. Here we outline standardized methodologies that would allow specimens and clinical data collected from different studies to be integrated and accessible to the IPF research community for investigations which will inform future basic and translational research in IPF. Such a biorepository needs the combined efforts of all stakeholders, to be driven by projected future scientific needs and to be available to all qualified researchers. We believe this infrastructure is crucial, is feasible, and would accelerate research in IPF.
    08/2014; 11(8). DOI:10.1513/AnnalsATS.201406-289OI
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    ABSTRACT: Background: The feasibility of an interventional clinical trial in idiopathic pulmonary fibrosis (IPF) using death and hospitalization as primary end points is an area of uncertainty. Using data from a large well-characterized clinical trial population, this article aims to illustrate the impact of cohort enrichment and study duration on sample size requirements for IPF clinical trials in which death alone or death plus hospitalization serve as the primary end point. Methods: Event rate estimates for death and hospitalization were determined from patients enrolled in National Institutes of Health-sponsored IPF Clinical Research Network clinical trials. Standard equations were applied to estimate the total sample size required for varying gender, age, and pulmonary function (GAP) stage-based cohorts. Results: Risk estimates for death and hospitalization in the clinical trial cohort were substantially lower than those published. An IPF trial with death as its primary end point enrolling subjects designated as GAP stage 1 and 2 over 1 year with a minimum follow-up of 1 year would require an estimated 7,986 subjects to achieve 90% power for a hazard ratio of 0.70. Alternatively, an IPF trial with death plus hospitalization as its primary end point enrolling subjects with GAP stage 2 and 3 over 2 years with a minimum follow-up of 1 year would require an estimated 794 subjects for the same power and hazard ratio. Conclusions: Study design decisions, in particular cohort enrichment strategies, have a substantial impact on sample size requirements for IPF clinical trials using time-to-event primary end points such as death and death plus hospitalization.
    Chest 08/2014; 146(5). DOI:10.1378/chest.14-0492 · 7.48 Impact Factor

Publication Stats

11k Citations
1,524.44 Total Impact Points


  • 2006-2015
    • National Jewish Health
      Denver, Colorado, United States
  • 2002-2015
    • University of Colorado
      • • Department of Medicine
      • • Division of Pulmonary Sciences and Critical Care Medicine
      Denver, Colorado, United States
    • Max Planck Institute for Mathematics in the Sciences
      Leipzig, Saxony, Germany
  • 2006-2009
    • National Research Center (CO, USA)
      Boulder, Colorado, United States
  • 2007
    • National Institute of Environmental Health Sciences
      • Laboratory of Respiratory Biology (LRB)
      Durham, North Carolina, United States
  • 2002-2006
    • Duke University
      Durham, North Carolina, United States
  • 2005
    • University of Michigan
      Ann Arbor, Michigan, United States
  • 2004
    • Yamaguchi University
      • Division of Radiology
      Yamaguti, Yamaguchi, Japan
  • 2003
    • University of Colorado Hospital
      Denver, Colorado, United States