Towards automatic pulmonary nodule management in lung cancer screening with deep learning

The introduction of lung cancer screening programs will produce an unprecedented amount of chest CT scans in the near future, which radiologists will have to read in order to decide on a patient follow-up strategy. According to the current guidelines, the workup of screen-detected nodules strongly relies on nodule size and nodule type. In this paper, we present a deep learning system based on multi-stream multi-scale convolutional networks, which automatically classifies all nodule types relevant for nodule workup. The system processes raw CT data containing a nodule without the need for any additional information such as nodule segmentation or nodule size and learns a representation of 3D data by analyzing an arbitrary number of 2D views of a given nodule. The deep learning system was trained with data from the Italian MILD screening trial and validated on an independent set of data from the Danish DLCST screening trial. We analyze the advantage of processing nodules at multiple scales with a multi-stream convolutional network architecture, and we show that the proposed deep learning system achieves performance at classifying nodule type that surpasses the one of classical machine learning approaches and is within the inter-observer variability among four experienced human observers.Comment: Published on Scientific Report

Pricing and cost-saving potential for deep-learning computer-aided lung nodule detection software in CT lung cancer screening

OBJECTIVE: An increasing number of commercial deep learning computer-aided detection (DL-CAD) systems are available but their cost-saving potential is largely unknown. This study aimed to gain insight into appropriate pricing for DL-CAD in different reading modes to be cost-saving and to determine the potentially most cost-effective reading mode for lung cancer screening.METHODS: In three representative settings, DL-CAD was evaluated as a concurrent, pre-screening, and second reader. Scoping review was performed to estimate radiologist reading time with and without DL-CAD. Hourly cost of radiologist time was collected for the USA (€196), UK (€127), and Poland (€45), and monetary equivalence of saved time was calculated. The minimum number of screening CTs to reach break-even was calculated for one-time investment of €51,616 for DL-CAD.RESULTS: Mean reading time was 162 (95% CI: 111-212) seconds per case without DL-CAD, which decreased by 77 (95% CI: 47-107) and 104 (95% CI: 71-136) seconds for DL-CAD as concurrent and pre-screening reader, respectively, and increased by 33-41 s for DL-CAD as second reader. This translates into €1.0-4.3 per-case cost for concurrent reading and €0.8-5.7 for pre-screening reading in the USA, UK, and Poland. To achieve break-even with a one-time investment, the minimum number of CT scans was 12,300-53,600 for concurrent reader, and 9400-65,000 for pre-screening reader in the three countries.CONCLUSIONS: Given current pricing, DL-CAD must be priced substantially below €6 in a pay-per-case setting or used in a high-workload environment to reach break-even in lung cancer screening. DL-CAD as pre-screening reader shows the largest potential to be cost-saving.CRITICAL RELEVANCE STATEMENT: Deep-learning computer-aided lung nodule detection (DL-CAD) software must be priced substantially below 6 euro in a pay-per-case setting or must be used in high-workload environments with one-time investment in order to achieve break-even. DL-CAD as a pre-screening reader has the greatest cost savings potential.KEY POINTS: • DL-CAD must be substantially below €6 in a pay-per-case setting to reach break-even. • DL-CAD must be used in a high-workload screening environment to achieve break-even. • DL-CAD as a pre-screening reader shows the largest potential to be cost-saving.</p

Amino Acid Function and Docking Site Prediction Through Combining Disease Variants, Structure Alignments, Sequence Alignments, and Molecular Dynamics: A Study of the HMG Domain

Background: The DNA binding domain of HMG proteins is known to be important in many diseases, with the Sox sub-family of HMG proteins of particular significance. Numerous natural variants in HMG proteins are associated with disease phenotypes. Integrating these natural variants, molecular dynamic simulations of DNA interaction and sequence and structure alignments give detailed molecular knowledge of potential amino acid function such as DNA or protein interaction. Results: A total of 33 amino acids in HMG proteins are known to have natural variants in diseases. Eight of these amino acids are normally conserved in human HMG proteins and 27 are conserved in the human Sox sub-family. Among the six non-Sox conserved amino acids, amino acids 16 and 45 are likely targets for interaction with other proteins. Docking studies between the androgen receptor and Sry/Sox9 reveals a stable amino acid specific interaction involving several Sox conserved residues. Conclusion: The HMG box has structural conservation between the first two of the three helixes in the domain as well as some DNA contact points. Individual sub-groups of the HMG family have specificity in the location of the third helix, DNA specific contact points (such as amino acids 4 and 29), and conserved amino acids interacting with other proteins such as androgen receptor. Studies such as this help to distinguish individual members of a much larger family of proteins and can be applied to any protein family of interest

Using urban climate modelling and improved land use classifications to support climate change adaptation in urban environments: A case study for the city of Klagenfurt, Austria

This study outlines the results of current and future climate scenarios, and potentially realizable climate adaptation measures, for the city of Klagenfurt, Austria. For this purpose, we used the microscale urban climate model (MUKLIMO_3), in conjunction with the cuboid method, to calculate climate indices such as the average number of summer and hot days per year. For the baseline simulation, we used meteorological measurements from 1981 to 2010 from the weather station located at Klagenfurt Airport. Individual building structures and canopy cover from several land monitoring services were used to derive accurate properties for land use classes in the study domain. To characterize the effectiveness of climate adaptation strategies, we compared changes in the climate indices for several (future) climate adaptation scenarios to the reference simulation. Specifically, we considered two major adaptation pathways: (i) an increase in the albedo values of sealed areas (i.e., roofs, walls and streets) and (ii) an increase in green surfaces (i.e., lawns on streets and at roof level) and high vegetated areas (i.e., trees). The results indicate that some climate adaptation measures show higher potential in mitigating hot days than others, varying between reductions of 2.3 to 11.0%. An overall combination of adaptation measures leads to a maximum reduction of up to 44.0%, indicating a clear potential for reduction/mitigation of urban heat loads. Furthermore, the results for the future scenarios reveal the possibility to remain at the current level of urban heat load during the daytime over the next three decades for the overall combination of measures

From Rat to Human: Regulation of Renin-Angiotensin System Genes by Sry

The testis determining protein, Sry, has functions outside of testis determination. Multiple Sry loci are found on the Y-chromosome. Proteins from these loci have differential activity on promoters of renin-angiotensin system genes, possibly contributing to elevation of blood pressure. Variation at amino acid 76 accounts for the majority of differential effects by rat proteins Sry1 and Sry3. Human SRY regulated rat promoters in the same manner as rat Sry, elevating Agt, Ren, and Ace promoter activity while downregulating Ace 2. Human SRY significantly regulated human promoters of AGT, REN, ACE2, AT2, and MAS compared to control levels, elevating AGT and REN promoter activity while decreasing ACE2, AT2, and MAS. While the effect of human SRY on individual genes is often modest, we show that many different genes participating in the renin-angiotensin system can be affected by SRY, apparently in coordinated fashion, to produce more Ang II and less Ang-(1–7)

Analysis of Sry Duplications On the Rattus Norvegicus Y-Chromosome

Background: Gene copy number variation plays a large role in the evolution of genomes. In Rattus norvegicus and other rodent species, the Y-chromosome has accumulated multiple copies of Sry loci. These copy number variations have been previously linked with changes in phenotype of animal models such as the spontaneously hypertensive rat (SHR). This study characterizes the Y-chromosome in the Sry region of Rattus norvegicus, while addressing functional variations seen in the Sry protein products. Results: Eleven Sry loci have been identified in the SHR with one (nonHMG Sry) containing a frame shift mutation. The nonHMGSry is found and conserved in the related WKY and SD rat strains. Three new, previously unidentified, Sry loci were identified in this study (Sry3BII, Sry4 and Sry4A) in both SHR and WKY. Repetitive element analysis revealed numerous LINE-L1 elements at regions where conservation is lost among the Sry copies. In addition we have identified a retrotransposed copy of Med14 originating from spliced mRNA, two autosomal genes (Ccdc110 and HMGB1) and a normal mammalian Y-chromosome gene (Zfy) in the Sry region of the rat Y-chromosome. Translation of the sequences of each Sry gene reveals eight proteins with amino acid differences leading to changes in nuclear localization and promoter activation of a Sry-responsive gene. Sry-beta (coded by the Sry2 locus) has an increased cytoplasmic fraction due to alterations at amino acid 21. Sry gamma has altered gene regulation of the Sry1 promoter due to changes at amino acid 76. Conclusions: The duplication of Sry on the Rattus norvegicus Y-chromosome has led to proteins with altered functional ability that may have been selected for functions in addition to testis determination. Additionally, several other genes not normally found on the Y-chromosome have duplicated new copies into the region around the Sry genes. These suggest a role of active transposable elements in the evolution of the mammalian Y-chromosome in species such as Rattus norvegicus