CovRadar: continuously tracking and filtering SARS-CoV-2 mutations for genomic surveillance.

SUMMARY: The ongoing pandemic caused by SARS-CoV-2 emphasizes the importance of genomic surveillance to understand the evolution of the virus, to monitor the viral population, and plan epidemiological responses. Detailed analysis, easy visualization and intuitive filtering of the latest viral sequences are powerful for this purpose. We present CovRadar, a tool for genomic surveillance of the SARS-CoV-2 Spike protein. CovRadar consists of an analytical pipeline and a web application that enable the analysis and visualization of hundreds of thousand sequences. First, CovRadar extracts the regions of interest using local alignment, then builds a multiple sequence alignment, infers variants and consensus and finally presents the results in an interactive app, making accessing and reporting simple, flexible and fast. AVAILABILITY AND IMPLEMENTATION: CovRadar is freely accessible at https://covradar.net, its open-source code is available at https://gitlab.com/dacs-hpi/covradar. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Human Observer Net: A Platform Tool for Human Observer Studies of Image Data.

Background Current software applications for human observer studies of images lack flexibility in study design, platform independence, multicenter use, and assessment methods and are not open source, limiting accessibility and expandability. Purpose To develop a user-friendly software platform that enables efficient human observer studies in medical imaging with flexibility of study design. Materials and Methods Software for human observer imaging studies was designed as an open-source web application to facilitate access, platform-independent usability, and multicenter studies. Different interfaces for study creation, participation, and management of results were implemented. The software was evaluated in human observer experiments between May 2019 and March 2021, in which duration of observer responses was tracked. Fourteen radiologists evaluated and graded software usability using the 100-point system usability scale. The application was tested in Chrome, Firefox, Safari, and Edge browsers. Results Software function was designed to allow visual grading analysis (VGA), multiple-alternative forced-choice (m-AFC), receiver operating characteristic (ROC), localization ROC, free-response ROC, and customized designs. The mean duration of reader responses per image or per image set was 6.2 seconds ± 4.8 (standard deviation), 5.8 seconds ± 4.7, 8.7 seconds ± 5.7, and 6.0 seconds ± 4.5 in four-AFC with 160 image quartets per reader, four-AFC with 640 image quartets per reader, localization ROC, and experimental studies, respectively. The mean system usability scale score was 83 ± 11 (out of 100). The documented code and a demonstration of the application are available online (https://github.com/genskeu/HON, https://hondemo.pythonanywhere.com/). Conclusion A user-friendly and efficient open-source application was developed for human reader experiments that enables study design versatility, as well as platform-independent and multicenter usability. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Thompson in this issue.

Deep learning reconstruction improves radiomics feature stability and discriminative power in abdominal CT imaging: a phantom study.

OBJECTIVES: To compare image quality of deep learning reconstruction (AiCE) for radiomics feature extraction with filtered back projection (FBP), hybrid iterative reconstruction (AIDR 3D), and model-based iterative reconstruction (FIRST). METHODS: Effects of image reconstruction on radiomics features were investigated using a phantom that realistically mimicked a 65-year-old patient's abdomen with hepatic metastases. The phantom was scanned at 18 doses from 0.2 to 4 mGy, with 20 repeated scans per dose. Images were reconstructed with FBP, AIDR 3D, FIRST, and AiCE. Ninety-three radiomics features were extracted from 24 regions of interest, which were evenly distributed across three tissue classes: normal liver, metastatic core, and metastatic rim. Features were analyzed in terms of their consistent characterization of tissues within the same image (intraclass correlation coefficient ≥ 0.75), discriminative power (Kruskal-Wallis test p value < 0.05), and repeatability (overall concordance correlation coefficient ≥ 0.75). RESULTS: The median fraction of consistent features across all doses was 6%, 8%, 6%, and 22% with FBP, AIDR 3D, FIRST, and AiCE, respectively. Adequate discriminative power was achieved by 48%, 82%, 84%, and 92% of features, and 52%, 20%, 17%, and 39% of features were repeatable, respectively. Only 5% of features combined consistency, discriminative power, and repeatability with FBP, AIDR 3D, and FIRST versus 13% with AiCE at doses above 1 mGy and 17% at doses ≥ 3 mGy. AiCE was the only reconstruction technique that enabled extraction of higher-order features. CONCLUSIONS: AiCE more than doubled the yield of radiomics features at doses typically used clinically. Inconsistent tissue characterization within CT images contributes significantly to the poor stability of radiomics features. KEY POINTS: • Image quality of CT images reconstructed with filtered back projection and iterative methods is inadequate for the majority of radiomics features due to inconsistent tissue characterization, low discriminative power, or low repeatability. • Deep learning reconstruction enhances image quality for radiomics and more than doubled the feature yield at doses that are typically used in clinical CT imaging. • Image reconstruction algorithms can optimize image quality for more reliable quantification of tissues in CT images.

Comparison of low-contrast detectability between uniform and anatomically realistic phantoms-influences on CT image quality assessment.

OBJECTIVES: To evaluate the effects of anatomical phantom structure on task-based image quality assessment compared with a uniform phantom background. METHODS: Two neck phantom types of identical shape were investigated: a uniform type containing 10-mm lesions with 4, 9, 18, 30, and 38 HU contrast to the surrounding area and an anatomically realistic type containing lesions of the same size and location with 10, 18, 30, and 38 HU contrast. Phantom images were acquired at two dose levels (CTDIvol of 1.4 and 5.6 mGy) and reconstructed using filtered back projection (FBP) and adaptive iterative dose reduction 3D (AIDR 3D). Detection accuracy was evaluated by seven radiologists in a 4-alternative forced choice experiment. RESULTS: Anatomical phantom structure impaired lesion detection at all lesion contrasts (p < 0.01). Detectability in the anatomical phantom at 30 HU contrast was similar to 9 HU contrast in uniform images (91.1% vs. 89.5%). Detection accuracy decreased from 83.6% at 5.6 mGy to 55.4% at 1.4 mGy in uniform FBP images (p < 0.001), whereas AIDR 3D preserved detectability at 1.4 mGy (80.7% vs. 85% at 5.6 mGy, p = 0.375) and was superior to FBP (p < 0.001). In the assessment of anatomical images, superiority of AIDR 3D was not confirmed and dose reduction moderately affected detectability (74.6% vs. 68.2%, p = 0.027 for FBP and 81.1% vs. 73%, p = 0.018 for AIDR 3D). CONCLUSIONS: A lesion contrast increase from 9 to 30 HU is necessary for similar detectability in anatomical and uniform neck phantom images. Anatomical phantom structure influences task-based assessment of iterative reconstruction and dose effects. KEY POINTS: • A lesion contrast increase from 9 to 30 HU is necessary for similar low-contrast detectability in anatomical and uniform neck phantom images. • Phantom background structure influences task-based assessment of iterative reconstruction and dose effects. • Transferability of CT assessment to clinical imaging can be expected to improve as the realism of the test environment increases.

Deep learning-based real-time detection of novel pathogens during sequencing.

Novel pathogens evolve quickly and may emerge rapidly, causing dangerous outbreaks or even global pandemics. Next-generation sequencing is the state of the art in open-view pathogen detection, and one of the few methods available at the earliest stages of an epidemic, even when the biological threat is unknown. Analyzing the samples as the sequencer is running can greatly reduce the turnaround time, but existing tools rely on close matches to lists of known pathogens and perform poorly on novel species. Machine learning approaches can predict if single reads originate from more distant, unknown pathogens but require relatively long input sequences and processed data from a finished sequencing run. Incomplete sequences contain less information, leading to a trade-off between sequencing time and detection accuracy. Using a workflow for real-time pathogenic potential prediction, we investigate which subsequences already allow accurate inference. We train deep neural networks to classify Illumina and Nanopore reads and integrate the models with HiLive2, a real-time Illumina mapper. This approach outperforms alternatives based on machine learning and sequence alignment on simulated and real data, including SARS-CoV-2 sequencing runs. After just 50 Illumina cycles, we observe an 80-fold sensitivity increase compared to real-time mapping. The first 250 bp of Nanopore reads, corresponding to 0.5 s of sequencing time, are enough to yield predictions more accurate than mapping the finished long reads. The approach could also be used for screening synthetic sequences against biosecurity threats.

Task-based assessment of neck CT protocols using patient-mimicking phantoms-effects of protocol parameters on dose and diagnostic performance.

OBJECTIVES: To assess how modifying multiple protocol parameters affects the dose and diagnostic performance of a neck CT protocol using patient-mimicking phantoms and task-based methods. METHODS: Six patient-mimicking neck phantoms containing hypodense lesions of 1 cm diameter and 30 HU contrast and one non-lesion phantom were examined with 36 CT protocols. All possible combinations of the following parameters were investigated: 100- and 120-kVp tube voltage; tube current modulation (TCM) noise levels of SD 7.5, 10, and 14; pitches of 0.637, 0.813, and 1.388; filtered back projection (FBP); and iterative reconstruction (AIDR 3D). Dose-length products (DLPs) and lesion detectability (assessed by 14 radiologists) were compared with the clinical standard protocol (120 kVp, TCM SD 7.5, 0.813 pitch, AIDR 3D). RESULTS: The DLP of the standard protocol was 25 mGy•cm; the area under the curve (AUC) was 0.839 (95%CI: 0.790-0.888). Combined effects of tube voltage reduction to 100 kVp and TCM noise level increase to SD 10 optimized protocol performance by improving dose (7.3 mGy•cm) and detectability (AUC 0.884, 95%CI: 0.844-0.924). Diagnostic performance was significantly affected by the TCM noise level at 120 kVp (AUC 0.821 at TCM SD 7.5 vs. 0.776 at TCM SD 14, p = 0.003), but not at 100-kVp tube voltage (AUC 0.839 at TCM SD 7.5 vs. 0.819 at TCM SD 14, p = 0.354), the reconstruction method at 100 kVp (AUC 0.854 for AIDR 3D vs. 0.806 for FBP, p < 0.001), but not at 120-kVp tube voltage (AUC 0.795 for AIDR 3D vs. 0.793 for FBP, p = 0.822), and the tube voltage for AIDR 3D reconstruction (p < 0.001), but not for FBP (p = 0.226). CONCLUSIONS: Combined effects of 100-kVp tube voltage, TCM noise level of SD 10, a pitch of 0.813, and AIDR 3D resulted in an optimal neck protocol in terms of dose and diagnostic performance. Protocol parameters were subject to complex interactions, which created opportunities for protocol improvement. KEY POINTS: • A task-based approach using patient-mimicking phantoms was employed to optimize a CT system for neck imaging through systematic testing of protocol parameters. • Combined effects of 100-kVp tube voltage, TCM noise level of SD 10, a pitch of 0.813, and AIDR 3D reconstruction resulted in an optimal protocol in terms of dose and diagnostic performance. • Interactions of protocol parameters affect diagnostic performance and should be considered when optimizing CT techniques.

3D printing of anatomically realistic phantoms with detection tasks to assess the diagnostic performance of CT images.

OBJECTIVES: Detectability experiments performed to assess the diagnostic performance of computed tomography (CT) images should represent the clinical situation realistically. The purpose was to develop anatomically realistic phantoms with low-contrast lesions for detectability experiments. METHODS: Low-contrast lesions were digitally inserted into a neck CT image of a patient. The original and the manipulated CT images were used to create five phantoms: four phantoms with lesions of 10, 20, 30, and 40 HU contrast and one phantom without any lesion. Radiopaque 3D printing with potassium-iodide-doped ink (600 mg/mL) was used. The phantoms were scanned with different CT settings. Lesion contrast was analyzed using HU measurement. A 2-alternative forced choice experiment was performed with seven radiologists to study the impact of lesion contrast on detection accuracy and reader confidence (1 = lowest, 5 = highest). RESULTS: The phantoms reproduced patient size, shape, and anatomy. Mean ± SD contrast values of the low-contrast lesions were 9.7 ± 1.2, 18.2 ± 2, 30.2 ± 2.7, and 37.7 ± 3.1 HU for the 10, 20, 30, and 40 HU contrast lesions, respectively. Mean ± SD detection accuracy and confidence values were not significantly different for 10 and 20 HU lesion contrast (82.1 ± 6.3% vs. 83.9 ± 9.4%, p = 0.863 and 1.7 ± 0.4 vs. 1.8 ± 0.5, p = 0.159). They increased to 95 ± 5.7% and 2.6 ± 0.7 for 30 HU lesion contrast and 99.5 ± 0.9% and 3.8 ± 0.7 for 40 HU lesion contrast (p < 0.005). CONCLUSIONS: A CT image was manipulated to produce anatomically realistic phantoms for low-contrast detectability experiments. The phantoms and our initial experiments provide a groundwork for the assessment of CT image quality in a clinical context. KEY POINTS: • Phantoms generated from manipulated CT images provide patient anatomy and can be used for detection tasks to evaluate the diagnostic performance of CT images. • Radiologists are unconfident and unreliable in detecting hypodense lesions of 20 HU contrast and less in an anatomical neck background. • Detectability experiments with anatomically realistic phantoms can assess CT image quality in a clinical context.

Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice.

Inflammasomes are protein complexes that promote caspase activation, resulting in processing of IL-1ß and cell death, in response to infection and cellular stresses. Inflammasomes have been anticipated to contribute to autoimmunity. The New Zealand Black (NZB) mouse develops anti-erythrocyte Abs and is a model of autoimmune hemolytic anemia. These mice also develop anti-nuclear Abs typical of lupus. In this article, we show that NZB macrophages have deficient inflammasome responses to a DNA virus and fungal infection. Absent in melanoma 2 (AIM2) inflammasome responses are compromised in NZB by high expression of the AIM 2 antagonist protein p202, and consequently NZB cells had low IL-1ß output in response to both transfected DNA and mouse CMV infection. Surprisingly, we also found that a second inflammasome system, mediated by the NLR family, pyrin domain containing 3 (NLRP3) initiating protein, was completely lacking in NZB cells. This was due to a point mutation in an intron of the Nlrp3 gene in NZB mice, which generates a novel splice acceptor site. This leads to incorporation of a pseudoexon with a premature stop codon. The lack of full-length NLRP3 protein results in NZB being effectively null for Nlrp3, with no production of bioactive IL-1ß in response to NLRP3 stimuli, including infection with Candida albicans. Thus, this autoimmune strain harbors two inflammasome deficiencies, mediated through quite distinct mechanisms. We hypothesize that the inflammasome deficiencies in NZB alter the interaction of the host with both microflora and pathogens, promoting prolonged production of cytokines that contribute to development of autoantibodies.