Doctor of Philosophy in Experimental Medicine (PhD)
Identification of blood-based biomarkers to distinguish subtypes of interstitial lung disease
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
Background: Interstitial lung disease (ILD) is a collection of diseases that cause fibrosis and/or inflammation of lung parenchyma, often resulting in the adverse consequence of hypoxemia that can be alleviated by domiciliary oxygen. Objectives: 1) Derive and validate a risk model to predict new-onset exertional and resting hypoxemia in patients with ILD. 2) Identify oxygen guidelines worldwide and compare these to national domiciliary oxygen criteria. 3) Compare costs of domiciliary oxygen for patients with ILD and chronic obstructive pulmonary disease (COPD). Methods: 1) A multivariable model that predicted new-onset exertional and resting hypoxemia was derived and validated in international cohorts using time-varying Cox regression, with the final model optimizing Harrell's C-index and goodness-of-fit (GoF). 2) Clinical practice guidelines for domiciliary oxygen were identified and compared to oxygen criteria and funding source used by the 193 member countries in the United Nations obtained from an Internet-based literature review. 3) A retrospective chart review determined monthly costs of oxygen in ILD and COPD within a large domiciliary oxygen program from 2010-2017. Results: 1) The best-performing prediction model for both exertional and resting hypoxemia included age, body mass index, idiopathic pulmonary fibrosis diagnosis, percent-predicted forced vital capacity, and diffusing capacity of carbon monoxide. Good performance was exhibited for prediction of exertional (C-index=0.70, GoF=0.85) and resting hypoxemia (C-index=0.77, GoF=0.27) in the derivation cohort, with performance replicated in the validation cohort except for calibration for prediction of resting hypoxemia (GoF=0.001). 2) Guidelines for continuous oxygen were obtained for 30 respiratory societies and criteria for 46 countries with public funding for oxygen. No public funding was available in 145 countries (5.9 billion people). 3) Cost of oxygen declined after month 1 (ILD: ($202.57 ± $88.88 in month 1 versus $142.21 ± $59.01 in month 2-24, P
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Rationale: Systemic sclerosis (SSc) is frequently complicated by interstitial lung disease (ILD), which is associated with significant morbidity and mortality in this population. Measuring disease extent and progression of SSc-ILD is challenging, with recent studies suggesting potential utility of quantitative measurements from computed tomography (CT) scans. Our objective was to determine the associations of CT density-based measurements with physiological parameters, visual CT scores, and survival in patients with SSc-ILD.Methods: Patients with SSc-ILD and volumetric high-resolution CT images with ≤1.25mm slice thickness were retrospectively identified. Cardiothoracic radiologists with >5 years’ experience produced visual CT scores of ground-glass, reticulation, and honeycombing, to the nearest 5%. Visual fibrosis scores were calculated as the sum of reticulation and honeycombing. CT density measurements included high attenuation areas (HAA), skewness, kurtosis, and mean lung attenuation (MLA), which were determined after excluding large airways and blood vessels. Associations of qCT measures with pulmonary physiology, visual CT scores, and mortality were analyzed using Spearman rank correlation and Cox regression.Results: 502 CT scans and 1084 PFTs from 170 patients with SSc-ILD were included. Baseline HAA, skewness, kurtosis, and MLA were associated with FVC (p
Fibrotic interstitial lung diseases (ILDs) are characterized by inflammation and fibrosis of the pulmonary parenchyma. In addition to the primary symptoms of dyspnea and cough, many patients with fibrotic ILD experience extrapulmonary deficits that can interfere with their ability to stay active. This is a concern as the maintenance of physical activity plays an important part in independence and prevention of deconditioning in patients with fibrotic ILD. However, the impact of common extrapulmonary deficits on daily physical activity of these patients is not known.Accordingly, in chapter 2, we examined the impact of depression, anxiety, poor sleep quality, and pain on daily physical activity in a cohort of 111 patients with fibrotic ILD. Extrapulmonary deficits were assessed using the Hospital Anxiety and Depression Scale, the Pittsburgh Sleep Quality Index, and the Brief Pain Inventory short form. Patients' physical activity was monitored for seven consecutive days using waist and wrist tri-axial accelerometers, in addition to the self-reported International Physical Activity Questionnaire long form (IPAQ-LF). Although depression and pain were moderately associated with lower step count on unadjusted analysis, extrapulmonary deficits did not independently predict lower physical activity when adjusting for basic demographics and ILD severity. However, we identified higher pain severity to be an independent predictor of lower step count using a multivariable stepwise approach. This finding suggests that pain may be a potential area that could be targeted by interventions to help patients maintain physical activity.In chapter 3, we examined the validity of the IPAQ-LF and estimated the minimally important difference (MID) for moderate-to-vigorous physical activity (MVPA) in patients with fibrotic ILD. We found the IPAQ-LF to have acceptable validity based on its measurements having moderate-to-strong correlations with corresponding waist accelerometer data and relevant clinical outcomes. The MID for weekly MVPA was estimated to be less than 60 minutes/week using the anchor-based approach. This indicates that adding only 60 minutes of MVPA per week is a realistic goal that brings meaningful benefits to patients with fibrotic ILD and provides a goal threshold for future clinical trials.