Thursday, April 3, 2025
4/3/2025
The role of quantitative CT and radiomic biomarkers for precision medicine in pulmonary fibrosis - Idiopathic pulmonary fibrosis (IPF) remains deadly despite two FDA approved therapies. Modifiable intermediate molecular markers and other metrics for disease severity and progression remain unmet needs for aiding drug development and clinical decision-making. Advances in image analysis enable objective detection and quantitation of anatomy, while high-dimensional images can identify sub-visual characteristics, often termed radiomic features – often called Quantitative CT (QCT). Data-driven texture analysis is a previously validated method of QCT and a powerful prognostic marker. We seek to evaluate radiomic features alone and in conjunction with other disease dimensions for prognostication and response to treatment in IPF. The parent PRECISIONS project has completed Whole Genome Sequencing, RNA seq and proteomics on over 1,600 ILD cases recruited thru the Pulmonary Fibrosis Foundation Registry (PFF-PR) generating novel markers of disease progression. The PRECISIONS clinical trial tests the efficacy of N-acetylcysteine in 200 IPF patients with a TOLLIP polymorphism. However, follow-up quantitative CT is not currently included in the trial. Our overall objectives are to identify and validate radiologic features, and intermediate response to therapy, and understand where to position these powerful QCT markers. We hypothesize that DTA scores will enhance prediction of disease progression, in conjunction with molecular markers. This ancillary proposal will add CTs to the PRECISIONS trial cohort and use a registry UVA/Chicago real world cohort for replication. In Aim 1, we will validate quantitative CT and radiomic markers for disease progression by independent replication for prediction of progression. We will collect baseline and 1-year HRCTs in UVA/Chicago, and PRECISIONS trial participants to evaluate: a) the prognostic value of baseline quantitative CT and radiomic markers (i.e. DTA) in predicting time to progression, b) associations between changes in CT biomarkers on sequential CT and changes in 1-year FVC and DLCO, and c) change in CT associated with drug treatment. In Aim 2: We will determine if candidate genetic variants for IPF susceptibility and survival associate with DTA score and improve predictive performance for survival. We will perform a cross-sectional analysis of PFF-PR cases comparing quantitative CT and radiomic markers at baseline with and without “at risk” genotypes for association with severity, and progression (decline in FVC over time). Findings will be replicated in UVA/Chicago cohort and in the prospective PRECISIONS cohort. Lastly, in Aim 3, We will assess if DTA and radiomic markers are additive/synergistic with plasma protein and blood transcriptome markers for disease progression. We have chosen published markers from a 4-protein panel signature along with CCL18, as examples given their current level of replication and promise. Will also include our 25 gene FVC predictor for disease progression. Similar analyses as outlined in Aims 1 and 2 will determine their additive information value. Changes in transcriptome and plasma levels over time may also offer measures of drug response.
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