Improving the Efficacy of ACR TI-RADS Through Deep Learning-Based Descriptor Augmentation.

Thyroid nodules occur in up to 68% of people, 95% of which are benign. Of the 5% of malignant nodules, many would not result in symptoms or death, yet 600,000 FNAs are still performed annually, with a PPV of 5-7% (up to 30%). Artificial intelligence (AI) systems have the capacity to improve diagnostic accuracy and workflow efficiency when integrated into clinical decision pathways. Previous studies have evaluated AI systems against physicians, whereas we aim to compare the benefits of incorporating AI into their final diagnostic decision. This work analyzed the potential for artificial intelligence (AI)-based decision support systems to improve physician accuracy, variability, and efficiency. The decision support system (DSS) assessed was Koios DS, which provides automated sonographic nodule descriptor predictions and a direct cancer risk assessment aligned to ACR TI-RADS. The study was conducted retrospectively between (08/2020) and (10/2020). The set of cases used included 650 patients (21% male, 79% female) of age 53 ± 15. Fifteen physicians assessed each of the cases in the set, both unassisted and aided by the DSS. The order of the reading condition was randomized, and reading blocks were separated by a period of 4 weeks. The system's impact on reader accuracy was measured by comparing the area under the ROC curve (AUC), sensitivity, and specificity of readers with and without the DSS with FNA as ground truth. The impact on reader variability was evaluated using Pearson's correlation coefficient. The impact on efficiency was determined by comparing the average time per read. There was a statistically significant increase in average AUC of 0.083 [0.066, 0.099] and an increase in sensitivity and specificity of 8.4% [5.4%, 11.3%] and 14% [12.5%, 15.5%], respectively, when aided by Koios DS. The average time per case decreased by 23.6% (p = 0.00017), and the observed Pearson's correlation coefficient increased from r = 0.622 to r = 0.876 when aided by Koios DS. These results indicate that providing physicians with automated clinical decision support significantly improved diagnostic accuracy, as measured by AUC, sensitivity, and specificity, and reduced inter-reader variability and interpretation times.

Stochastic motion and transcriptional dynamics of pairs of distal DNA loci on a compacted chromosome.

Chromosomes in the eukaryotic nucleus are highly compacted. However, for many functional processes, including transcription initiation, the 3D pair-wise motion of distal chromosomal elements, such as enhancers and promoters, is essential and necessitates dynamic fluidity. Therefore, the interplay of chromosome organization and dynamics is crucial for gene regulation. Here, we use a live imaging assay to simultaneously measure the positions of pairs of enhancers and promoters and their transcriptional output in the developing fly embryo while systematically varying the genomic separation between these two DNA loci. Our analysis reveals a combination of a compact globular organization and fast subdiffusive dynamics. These combined features cause an anomalous scaling of polymer relaxation times with genomic separation and lead to long-ranged correlations compared to existing polymer models. This scaling implies that encounter times of DNA loci are much less dependent on genomic separation than predicted by existing polymer models, with potentially significant consequences for eukaryotic gene expression.

Stochastic motion and transcriptional dynamics of pairs of distal DNA loci on a compacted chromosome.

Chromosomes in the eukaryotic nucleus are highly compacted. However, for many functional processes, including transcription initiation, the pairwise motion of distal chromosomal elements such as enhancers and promoters is essential and necessitates dynamic fluidity. Here, we used a live-imaging assay to simultaneously measure the positions of pairs of enhancers and promoters and their transcriptional output while systematically varying the genomic separation between these two DNA loci. Our analysis reveals the coexistence of a compact globular organization and fast subdiffusive dynamics. These combined features cause an anomalous scaling of polymer relaxation times with genomic separation leading to long-ranged correlations. Thus, encounter times of DNA loci are much less dependent on genomic distance than predicted by existing polymer models, with potential consequences for eukaryotic gene expression.

Dynamic interplay between enhancer-promoter topology and gene activity.

A long-standing question in gene regulation is how remote enhancers communicate with their target promoters, and specifically how chromatin topology dynamically relates to gene activation. Here, we combine genome editing and multi-color live imaging to simultaneously visualize physical enhancer-promoter interaction and transcription at the single-cell level in Drosophila embryos. By examining transcriptional activation of a reporter by the endogenous even-skipped enhancers, which are located 150 kb away, we identify three distinct topological conformation states and measure their transition kinetics. We show that sustained proximity of the enhancer to its target is required for activation. Transcription in turn affects the three-dimensional topology as it enhances the temporal stability of the proximal conformation and is associated with further spatial compaction. Furthermore, the facilitated long-range activation results in transcriptional competition at the locus, causing corresponding developmental defects. Our approach offers quantitative insight into the spatial and temporal determinants of long-range gene regulation and their implications for cellular fates.