Tracy J Doyle

Brigham and Women's Hospital, Boston, Massachusetts, United States

Are you Tracy J Doyle?

Claim your profile

Publications (12)90.36 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Evidence suggests that individuals with interstitial lung abnormalities (ILA) on a chest computed tomogram (CT) may have an increased risk to develop a clinically significant interstitial lung disease (ILD). Although methods used to identify individuals with ILA on chest CT have included both automated quantitative and qualitative visual inspection methods, there has been not direct comparison between these two methods. To investigate this relationship, we created lung density metrics and compared these to visual assessments of ILA. Methods To provide a comparison between ILA detection methods based on visual assessment we generated measures of high attenuation areas (HAAs, defined by attenuation values between −600 and −250 Hounsfield Units) in >4500 participants from both the COPDGene and Framingham Heart studies (FHS). Linear and logistic regressions were used for analyses. Results Increased measures of HAAs (in ≥10 % of the lung) were significantly associated with ILA defined by visual inspection in both cohorts (P < 0.0001); however, the positive predictive values were not very high (19 % in COPDGene and 13 % in the FHS). In COPDGene, the association between HAAs and ILA defined by visual assessment were modified by the percentage of emphysema and body mass index. Although increased HAAs were associated with reductions in total lung capacity in both cohorts, there was no evidence for an association between measurement of HAAs and MUC5B promoter genotype in the FHS. Conclusion Our findings demonstrate that increased measures of lung density may be helpful in determining the severity of lung volume reduction, but alone, are not strongly predictive of ILA defined by visual assessment. Moreover, HAAs were not associated with MUC5B promoter genotype.
    No preview · Article · Oct 2015 · BMC Pulmonary Medicine
  • [Show abstract] [Hide abstract]
    ABSTRACT: Non-cardiac thoracic manifestations of rheumatoid arthritis (RA) cause significant morbidity and mortality among RA patients. Essentially all anatomic compartments in the chest can be affected including the pleura, pulmonary parenchyma, airway, and vasculature. In addition, treatment-related complications and opportunistic infections are not uncommon. Accurate diagnosis of intra-thoracic disease in an RA patient can be difficult as the radiologic findings may be nonspecific and many of these conditions may coexist. This review article serves to highlight the multitude of RA-related intra-thoracic pathological processes, emphasize differential diagnosis, diagnostic conundrums and discuss how tailoring of CT imaging and image-guided biopsy plays a key role in the management of RA-related pulmonary disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    No preview · Article · Jul 2015 · European journal of radiology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is under-recognized. To identify clinical risk factors, autoantibodies, and biomarkers associated with the presence of RA-ILD. Subjects enrolled in BRASS and ACR cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA-ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR. 113 BRASS subjects with clinically-indicated chest CT scans (41% with a spectrum of clinically-evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51% with a spectrum of RA-ILD) were selected. A combination of age, gender, smoking, rheumatoid factor, and anti-cyclic citrullinated peptide antibodies was strongly associated with RA-ILD (AUCs 0.88/BRASS and 0.89/ACR). Importantly a combinatorial signature including MMP7, PARC, and SP-D significantly increased the AUCs to 0.97 (p=0.002/BRASS) and 1.00 (p=0.016/ACR). Similar trends were seen for both clinically-evident and subclinical RA-ILD. Clinical risk factors and autoantibodies are strongly associated with the presence of clinically-evident and subclinical RA-ILD on CT scan in two independent RA cohorts. A biomarker signature composed of MMP7, PARC, and SP-D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality.
    No preview · Article · Mar 2015 · American Journal of Respiratory and Critical Care Medicine
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Interstitial lung disease (ILD) is a relatively common extraarticular manifestation of rheumatoid arthritis (RA) that contributes significantly to disease burden and excess mortality. The purpose of this study was to identify peripheral blood markers of RA-associated ILD that can facilitate earlier diagnosis and provide insight regarding the pathogenesis of this potentially devastating disease complication. Methods: Patients with RA who were enrolled in a well-characterized Chinese identification cohort or a US replication cohort were subclassified as having RA-no ILD, RA-mild ILD, or RA-advanced ILD, based on high-resolution computed tomography scans of the chest. Multiplex enzyme-linked immunosorbent assays (ELISAs) and Luminex xMAP technology were used to assess 36 cytokines/chemokines, matrix metalloproteinases (MMPs), and acute-phase proteins in the identification cohort. Unadjusted and adjusted logistic regression models were used to quantify the strength of association between RA-ILD and biomarkers of interest. Results: MMP-7 and interferon-γ-inducible protein 10 (IP-10)/CXCL10 were identified by multiplex ELISA as potential biomarkers for RA-ILD in 133 RA patients comprising the Chinese identification cohort (50 RA-no ILD, 41 RA-ILD, 42 RA-indeterminate ILD). The findings were confirmed by standard solid-phase sandwich ELISA in the Chinese identification cohort as well as an independent cohort of US patients with RA and different stages of ILD (22 RA-no ILD, 49 RA-ILD, 15 RA-indeterminate ILD), with statistically significant associations in both unadjusted and adjusted logistic regression analyses. Conclusion: Levels of MMP-7 and IP-10/CXCL10 are elevated in the serum of RA patients with ILD, whether mild or advanced, supporting their value as pathogenically relevant biomarkers that can contribute to noninvasive detection of this extraarticular disease complication.
    No preview · Article · Jan 2015 · Arthritis and Rheumatology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Previous work has demonstrated a correlation between serum anti-citrullinated HSP90 antibodies and rheumatoid arthritis-associated interstitial lung disease (RA-ILD). To further investigate this potential pathogenic relationship, we used ELISA-based techniques to assess anti-citrullinated HSP90 antibody profiles in bronchoalveolar lavage fluid (BALF) of patients with different stages of RA-ILD. 9/21 RA-derived BALF specimens demonstrated IgG and/or IgA antibodies targeting citrullinated HSP90 proteins/peptides, highlighting disease specific responses (with a predilection for RA-ILD) that did not occur in IPF patients (0/5) or healthy control subjects (0/5). Comparison of antibody profiles between BALF and matching serum specimens revealed various recognition patterns favoring predominant production of anti-citrullinated HSP90 antibodies within the lung microenvironment-further supporting the connection between this antibody specificity and parenchymal lung disease. Equally important, qualitative as well as quantitative differences in anti-citrullinated HSP90 profiles between BALF and serum indicate that the lung plays a direct role in shaping the immune repertoire of RA/RA-ILD.
    No preview · Article · Aug 2014 · Clinical Immunology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rheumatoid arthritis (RA) is a systemic inflammatory disorder affecting approximately 1.3 million adults in the United States. Approximately 10% of these individuals with RA have clinically evident interstitial lung disease (RA-ILD), and an additional one-third demonstrate subclinical ILD on chest CT scan. The risk of death for individuals with RA-ILD is three times higher than for patients with RA without ILD, with a median survival after ILD diagnosis of only 2.6 years. Despite the high prevalence and mortality of RA-ILD, little is known about its molecular features and its natural history. At present, we lack a standard validated approach to the definition, diagnosis, risk stratification, and management of RA-ILD. In this perspective, we discuss the importance of clinical and translational research and how ongoing research efforts can address important gaps in our knowledge over the next few years. Furthermore, recommendations are made to design multicenter collaborative studies that will expedite the development of clinical trials designed to decrease the significant morbidity and mortality associated with RA-ILD.
    No preview · Article · Mar 2014 · Chest
  • [Show abstract] [Hide abstract]
    ABSTRACT: Approximately 10% of rheumatoid arthritis (RA) patients have interstitial lung disease (ILD) and one-third have subclinical ILD on chest CT. In this study, we aim to further characterize functional decrements in a spectrum of RA-ILD. All subjects were enrolled in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS). The presence of interstitial lung abnormalities (ILA) on clinically indicated chest CT scans was determined using a previously validated sequential reading method. Univariate and multivariate analyses were used to assess the association between degree of ILA and physiologic, functional and demographic variables of interest. Ninety one (8%) from a total of 1145 BRASS subjects were included in this study; 12 had radiologically severe ILA, 34 had ILA, and 38 had no ILA on CT scan. Subjects with radiologically severe ILA were older (p=0.0037), had increased respiratory symptoms (cough p=0.027, dyspnea p=0.010), and more severe RA disease (rheumatoid factor p=0.018, total swollen joints p=0.046) compared to no ILA. Participants also had a trend toward being heavier smokers (p=0.16) and having lower FVC% (77% vs. 94%, p=0.097) and DLco% (52% vs. 77%, p=0.068). Similar, but attenuated, increases in respiratory symptoms, functional decrements, and RA disease severity were observed in subjects with ILA compared to no ILA. We have shown that RA patients have varying degrees of ILA that are associated with a spectrum of functional and physiologic decrements. Our findings suggest that improved risk-stratification and detection of ILA will provide a therapeutic window that could improve RA-ILD outcomes.
    No preview · Article · Dec 2013 · Chest
  • [Show abstract] [Hide abstract]
    ABSTRACT: Original Investigation SlidePRESENTED ON: Wednesday, October 30, 2013 at 02:45 PM - 03:45 PMPURPOSE: Cigarette smokers are at risk for developing IPF. Identifying at-risk individuals with subclinical interstitial lung disease could provide a better understanding of disease progression and earlier therapeutic interventions. As such, we hypothesized that a peripheral blood biomarker signature can identify patients with radiographic interstitial lung abnormalities (ILA).METHODS: CT scans and plasma samples were obtained from the Univ. of Pittsburgh Lung Screening Study (PluSS). CT scans were scored on a 0-3 scale (0=no evidence;1=indeterminate;2=ILA;3=fibrosis). We then examined plasma samples using multiplex technology for the expression of 126 proteins. Univariate analyses were performed to identify a specific signature in patients with ILA. In addition, the random forest method was used to assess the performance of classification based on overall patterns of all clinical parameters and bioanalytes. We chose the subset of smallest number of variables whose error rate was within the standard error of the minimum error rates of all forests. During each step, the least important variable would be deleted successively and stopped when the reduced and full models did not have similar performance. Out-of-bag error was reported.RESULTS: Of 415 patients, 148 had CT scores of 2 or 3 of which 80 were selected as cases. 150 controls with CT scores of 0 or 1 were matched for age, gender, race, and semi-quantitative assessment of CT emphysema. An analysis of the protein biomarker data with unadjusted ANCOVA identified 35 analytes that had significant differential expression in cases versus controls. After Bonferonni correction, 6 analytes remained significant: PARC, MIP-3α, SP-D, ICAM-1, E-selectin, CRP. The adjusted model for the above analytes yielded similar p values. Using random forest, a signature with 7 variables-age, emphysema score, MMP-7, PARC, SP-D, resistin, TNFRSF1A-is able to identify patients with ILA on CT with an 18.4% out-of-bag error. The performance of this model was similar to the model using all variables.CONCLUSIONS: Smokers with ILA on CT can be identified using a specific peripheral blood biomarker signature. Of significance, a number of proteins in the signature have also been shown to have increased expression and predict survival in patients with IPF.CLINICAL IMPLICATIONS: This biomarker signature, if validated, could serve as the basis for identifying subclinical pulmonary fibrosis in at-risk individuals. These individuals could then be monitored closely for development and progression of IPF.DISCLOSURE: The following authors have nothing to disclose: Avignat Patel, Tracy Doyle, Yushi Liu, Hiroto Hatabu, Mizuki Nishino Hatabu, Yuka Okajima, Cristobal Risquez, Yuanyuan Shi, Juan Osorio, Maria Golzarri, James Lederer, Souheil El-Chemaly, Victor Pinto-Plata, Bartolome Celli, Gary Hunninghake, George Washko, Frank Sciurba, Naftali Kaminski, Joseph Leader, Jill Siegfried, Joel Weissfeld, Ivan RosasNo Product/Research Disclosure Information.
    No preview · Article · Oct 2013 · Chest
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent advances in the field of clinical biomarkers suggest that quantification of serum proteins could play an important role in the diagnosis, classification, prognosis, and treatment response of smoking-related parenchymal lung diseases. COPD and idiopathic pulmonary fibrosis (IPF), two common chronic progressive parenchymal lung diseases, share cigarette smoke exposure as a common dominant risk factor for their development. We have recently shown that COPD and interstitial lung disease may represent distinct outcomes of chronic tobacco use, whereas others have demonstrated that both diseases coexist in some individuals. In this perspective, we examine the potential role of peripheral blood biomarkers in predicting which individuals will develop COPD or IPF, as well as their usefulness in tracking disease progression and exacerbations. Additionally, given the current lack of sensitive and effective metrics to determine an individual's response to treatment, we evaluate the potential role of biomarkers as surrogate markers of clinical outcomes. Finally, we examine the possibility that changes in levels of select protein biomarkers can provide mechanistic insight into the common origins and unique individual susceptibilities that lead to the development of smoking-related parenchymal lung diseases. This discussion is framed by a consideration of the properties of ideal biomarkers for different clinical and research purposes and the best uses for those biomarkers that have already been proposed and investigated. CHEST 2012; 142(4):1027-1034
    No preview · Article · Oct 2012 · Chest
  • Tracy J. Doyle · Gary M. Hunninghake · Ivan O. Rosas

    No preview · Article · Aug 2012 · American Journal of Respiratory and Critical Care Medicine
  • Tracy J Doyle · Gary M Hunninghake · Ivan O Rosas
    [Show abstract] [Hide abstract]
    ABSTRACT: The widespread use of high-resolution computed tomography in clinical and research settings has increased the detection of interstitial lung abnormalities (ILA) in asymptomatic and undiagnosed individuals. We reported that in smokers, ILA were present in about 1 of every 12 high-resolution computed tomographic scans; however, the long-term significance of these subclinical changes remains unclear. Studies in families affected with pulmonary fibrosis, smokers with chronic obstructive pulmonary disease, and patients with inflammatory lung disease have shown that asymptomatic and undiagnosed individuals with ILA have reductions in lung volume, functional limitations, increased pulmonary symptoms, histopathologic changes, and molecular profiles similar to those observed in patients with clinically significant interstitial lung disease (ILD). These findings suggest that, in select at-risk populations, ILA may represent early stages of pulmonary fibrosis or subclinical ILD. The growing interest surrounding this topic is motivated by our poor understanding of the inciting events and natural history of ILD, coupled with a lack of effective therapies. In this perspective, we outline past and current research focused on validating radiologic, physiological, and molecular methods to detect subclinical ILD. We discuss the limitations of the available cross-sectional studies and the need for future longitudinal studies to determine the prognostic and therapeutic implications of subclinical ILD in populations at risk of developing clinically significant ILD.
    Preview · Article · Feb 2012 · American Journal of Respiratory and Critical Care Medicine
  • [Show abstract] [Hide abstract]
    ABSTRACT: The relationship between interstitial lung abnormalities (ILA) and exercise capacity has not been comprehensively evaluated. To assess the validity of the 6-minute walk test in subjects with ILA, and to examine the association between ILA and 6-minute walk distance (6MWD). Spearman correlation coefficients were used to assess the strength of the relationships between 6MWD and relevant measures of dyspnea, health-related quality of life, and pulmonary function in a cohort of 2,416 people who smoke from the COPDGene study. Unadjusted and adjusted linear and logistic regression models were used to assess the strength of the association between ILA and 6MWD. In all subjects, and in those with ILA, 6MWD in COPDGene was associated with relevant clinical and physiologic measures. The mean 6MWD in COPDGene subjects with ILA was 386 m (SD, 128 m), and 82% and 19% of subjects with ILA had 6MWDs less than or equal to 500 and 250 m, respectively. ILA was associated with a reduced 6MWD in univariate (-30 m; 95% confidence interval, -50 to -10; P = 0.004) and multivariate models (-19 m; 95% confidence interval, -33 to -5; P = 0.008). Compared with subjects without ILA, subjects with ILA had an 80% and 77% increase in their odds to have a walk distance limited to less than or equal to 500 and 250 m, respectively. Although these findings were dependent on ILA subtype, they were not limited to those with COPD. Our study demonstrates that ILA is associated with measurable decrements in the 6MWD of people who smoke. Clinical trial registered with (NCT 00608764).
    Preview · Article · Jan 2012 · American Journal of Respiratory and Critical Care Medicine