Baseline Characteristics and Progression of a Spectrum of Interstitial Lung Abnormalities and Disease in Rheumatoid Arthritis.

BACKGROUND: Interstitial lung abnormalities (ILA) and interstitial lung disease (ILD) are seen in up to 60% of individuals with rheumatoid arthritis (RA), some of which will progress to have a significant impact on morbidity and mortality rates. Better characterization of progressive interstitial changes and identification of risk factors that are associated with progression may enable earlier intervention and improved outcomes. RESEARCH QUESTION: What are baseline characteristics associated with RA-ILD progression? STUDY DESIGN AND METHODS: We performed a retrospective study in which all clinically indicated CT chest scans in adult individuals with RA from 2014 to 2016 were evaluated for interstitial changes, and the data were further subdivided into ILA and ILD based on clinical record review. Progression was determined visually and subsequently semiquantified. RESULTS: Those individuals with a spectrum of interstitial changes (64 of 293) were older male smokers and less likely to be receiving biologics/small molecule disease-modifying antirheumatic drugs. Of 44% of the individuals with ILA, 46% had had chest CT scans performed for nonpulmonary indications. Of the 56 individuals with ILA/ILD with sequential CT scans, 38% had evidence of radiologic progression over 4.4 years; 29% of of individuals with ILA progressed. Risk factors for progressive ILA/ILD included a subpleural distribution and higher baseline involvement. INTERPRETATION: Of 293 individuals with RA with clinically indicated CT scans, interstitial changes were observed in 22%, one-half of whom had had a respiratory complaint at the time of imaging; radiologic progression was seen in 38%. Of individuals with progressive ILA, one-half had had baseline CT scans performed for nonpulmonary indications. Subpleural distribution and higher baseline ILA/ILD extent were risk factors associated with progression. Prospective longitudinal studies of RA-ILA are necessary.

Genome-wide discovery of human heart enhancers.

The various organogenic programs deployed during embryonic development rely on the precise expression of a multitude of genes in time and space. Identifying the cis-regulatory elements responsible for this tightly orchestrated regulation of gene expression is an essential step in understanding the genetic pathways involved in development. We describe a strategy to systematically identify tissue-specific cis-regulatory elements that share combinations of sequence motifs. Using heart development as an experimental framework, we employed a combination of Gibbs sampling and linear regression to build a classifier that identifies heart enhancers based on the presence and/or absence of various sequence features, including known and putative transcription factor (TF) binding specificities. In distinguishing heart enhancers from a large pool of random noncoding sequences, the performance of our classifier is vastly superior to four commonly used methods, with an accuracy reaching 92% in cross-validation. Furthermore, most of the binding specificities learned by our method resemble the specificities of TFs widely recognized as key players in heart development and differentiation, such as SRF, MEF2, ETS1, SMAD, and GATA. Using our classifier as a predictor, a genome-wide scan identified over 40,000 novel human heart enhancers. Although the classifier used no gene expression information, these novel enhancers are strongly associated with genes expressed in the heart. Finally, in vivo tests of our predictions in mouse and zebrafish achieved a validation rate of 62%, significantly higher than what is expected by chance. These results support the existence of underlying cis-regulatory codes dictating tissue-specific transcription in mammalian genomes and validate our enhancer classifier strategy as a method to uncover these regulatory codes.