
1.Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, Illinois, 61801, USA
2.Beckman Institute of Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois, 61801, USA
3.Department of Electrical and Computer Engineering, University of Illinois Urbana-Champaign, Urbana, Illinois, 61801, USA
4.Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
5.Department of Civil and Environmental Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
6.NCSA Center for Artificial Intelligence Innovation, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
7.Holonyak Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, USA
8.Biomedical Research Center, Carle Foundation Hospital, 509W University Ave., Urbana, Illinois, 61801, USA
9.Carle Illinois College of Medicine, 807 South Wright St., Urbana, Illinois, 61801, USA
10.Mayo-Illinois Alliance for Technology Based Healthcare, Urbana, Illinois, 61801, USA
11.Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
Gabriel Popescu(gpopescu@illinois.edu)
Published:30 September 2021,
Published Online:01 September 2021,
Received:10 March 2021,
Revised:03 August 2021,
Accepted:18 August 2021
Scan QR Code
Goswami N. H. et al. Label-free SARS-CoV-2 detection and classification using phase imaging with computational specificity. Light: Science & Applications, 10, 1797-1808 (2021).
Goswami N. H. et al. Label-free SARS-CoV-2 detection and classification using phase imaging with computational specificity. Light: Science & Applications, 10, 1797-1808 (2021). DOI: 10.1038/s41377-021-00620-8.
Efforts to mitigate the COVID-19 crisis revealed that fast
accurate
and scalable testing is crucial for curbing the current impact and that of future pandemics. We propose an optical method for directly imaging unlabeled viral particles and using deep learning for detection and classification. An ultrasensitive interferometric method was used to image four virus types with nanoscale optical path-length sensitivity. Pairing these data with fluorescence images for ground truth
we trained semantic segmentation models based on U-Net
a particular type of convolutional neural network. The trained network was applied to classify the viruses from the interferometric images only
containing simultaneously SARS-CoV-2
H1N1 (influenza-A virus)
HAdV (adenovirus)
and ZIKV (Zika virus). Remarkably
due to the nanoscale sensitivity in the input data
the neural network was able to identify SARS-CoV-2 vs. the other viruses with 96% accuracy. The inference time for each image is 60 ms
on a common graphic-processing unit. This approach of directly imaging unlabeled viral particles may provide an extremely fast test
of less than a minute per patient. As the imaging instrument operates on regular glass slides
we envision this method as potentially testing on patient breath condensates. The necessary high throughput can be achieved by translating concepts from digital pathology
where a microscope can scan hundreds of slides automatically.
Pfefferbaum, B.&North, C. S. Mental health and the COVID-19 pandemic.N. Engl. J. Med.383, 510–512 (2020)..
Douglas, M. et al. Mitigating the wider health effects of covid-19 pandemic response.BMJ369, m1557 (2020)..
Worobey, M. et al. The emergence of SARS-CoV-2 in Europe and North America.Science370, 564–570, https://doi.org/10.1126/science.abc8169 (2020)..
Weissleder, R. et al. COVID-19 diagnostics in context.Sci. Transl. Med.12, eabc1931, https://doi.org/10.1126/scitranslmed.abc1931 (2020)..
Ai, T. et al. Correlation of chest CT and RT-PCR Testing for coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases.Radiology296, E32–E40, https://doi.org/10.1148/radiol.2020200642 (2020)..
Moitra, P. et al. Selective naked-eye detection of SARS-CoV-2 mediated by N gene targeted antisense oligonucleotide capped plasmonic nanoparticles.ACS Nano14, 7617–7627 (2020)..
Murugan, D. et al. P-FAB: a fiber-optic biosensor device for rapid detection of COVID-19.Trans. Indian Natl Acad. Eng.5, 211–215 (2020)..
Peng, X. et al. Promising near-infrared plasmonic biosensor employed for specific detection of SARS-CoV-2 and its spike glycoprotein.New J. Phys.22, 103046 (2020)..
Shiaelis, N. et al. Virus detection and identification in minutes using single-particle imaging and deep learning.medRxiv. https://doi.org/10.1101/2020.10.13.20212035 (2020).
Lin, Q. Y. et al. Microfluidic immunoassays for sensitive and simultaneous detection of IgG/IgM/antigen of SARS-CoV-2 within 15 min.Anal. Chem.92, 9454–9458 (2020)..
Ray, A. et al. Computational sensing of herpes simplex virus using a cost-effective on-chip microscope.Sci. Rep.7, 4856 (2017)..
Lindfors, K. et al. Detection and spectroscopy of gold nanoparticles using supercontinuum white light confocal microscopy.Phys. Rev. Lett.93, 037401 (2004)..
Taylor, R. W.&Sandoghdar, V. Interferometric scattering microscopy: seeing single nanoparticles and molecules via rayleigh scattering.Nano Lett.19, 4827–4835 (2019)..
Spindler, S. et al. Visualization of lipids and proteins at high spatial and temporal resolution via interferometric scattering (iSCAT) microscopy.J. Phys. D Appl. Phys.49, 274002 (2016)..
Ignatovich, F. V.&Novotny, L. Real-time and background-free detection of nanoscale particles.Phys. Rev. Lett.96, 013901 (2006)..
Kukura, P. et al. High-speed nanoscopic tracking of the position and orientation of a single virus.Nat. Methods6, 923–927 (2009)..
Daaboul, G. et al. High-throughput detection and sizing of individual low-index nanoparticles and viruses for pathogen identification.Nano Lett.10, 4727–4731 (2010)..
Goldfain, A. M. et al. Dynamic measurements of the position, orientation, and DNA content of individual unlabeled bacteriophages.J. Phys. Chem. B120, 6130–6138 (2016)..
Popescu, G.Quantitative Phase Imaging of Cells and Tissues(McGraw Hill Professional, 2011).
Park, Y., Depeursinge, C.&Popescu, G. Quantitative phase imaging in biomedicine.Nat. Photonics12, 578–589 (2018)..
Ban, S. et al. Optical properties of acute kidney injury measured by quantitative phase imaging.Biomed. Opt. Express9, 921–932 (2018)..
Bertels, J. et al. Zinc's effect on the differentiation of porcine adipose-derived stem cells into osteoblasts.J. Regen. Med.8, 2 (2019)..
Fanous, M. et al. Quantitative phase imaging of stromal prognostic markers in pancreatic ductal adenocarcinoma.Biomed. Opt. Express11, 1354–1364 (2020)..
Hu, C. et al. Imaging collagen properties in the uterosacral ligaments of women with pelvic organ prolapse using spatial light interference microscopy (SLIM).Front. Phys.7, 72 (2019)..
Li, Y. et al. Quantitative phase imaging reveals matrix stiffness-dependent growth and migration of cancer cells.Sci. Rep.9, 248 (2019)..
Liu, L. et al. Topography and refractometry of sperm cells using spatial light interference microscopy.J. Biomed. Opt.23, 025003 (2018)..
Rubessa, M. et al. SLIM microscopy allows for visualization of DNA-containing liposomes designed for sperm-mediated gene transfer in cattle.Mol. Biol. Rep.46, 695–703 (2019)..
Merola, F. et al. Tomographic flow cytometry by digital holography.Light Sci. Appl.6, e16241, https://doi.org/10.1038/lsa.2016.241 (2017)..
Lee, M. et al. Label-free optical quantification of structural alterations in Alzheimer's disease.Sci. Rep.6, 31034 (2016)..
Eldridge, W. J. et al. Optical phase measurements of disorder strength link microstructure to cell stiffness.Biophysical J.112, 692–702 (2017)..
Nygate, Y. N. et al. Holographic virtual staining of individual biological cells.Proc. Natl Acad. Sci. USA117, 9223–9231, https://doi.org/10.1073/pnas.1919569117 (2020)..
Kim, T. et al. White-light diffraction tomography of unlabelled live cells.Nat. Photonics8, 256–263, https://doi.org/10.1038/nphoton.2013.350 (2014)..
Wang, Z. et al. Spatial light interference microscopy (SLIM).Opt. Express19, 1016–1026 (2011)..
Chen, X. et al. Wolf phase tomography (WPT) of transparent structures using partially coherent illumination.Light Sci. Appl.9, 142 (2020)..
Dey, N. et al. Richardson–Lucy algorithm with total variation regularization for 3D confocal microscope deconvolution.Microsc. Res. Tech.69, 260–266 (2006)..
Sage, D. et al. DeconvolutionLab2: an open-source software for deconvolution microscopy.Methods115, 28–41 (2017)..
Goldsmith, C. S.&Tamin, A.Electron microscopic image of a negatively stained particle of SARS-CoV-2, causative agent of COVID-19(2020).https://phil.cdc.gov/Details.aspx?pid=23640https://phil.cdc.gov/Details.aspx?pid=23640..
Prasad, S. et al. Transmission electron microscopy imaging of SARS-CoV-2.Indian J. Med. Res.151, 241–243 (2020)..
Centers for Disease Control and Prevention.Images of the H1N1 Influenza Virus(CDC, 2010).https://www.cdc.gov/h1n1flu/images.htmhttps://www.cdc.gov/h1n1flu/images.htm..
Ostapchuk, P. et al. The adenovirus major core protein VII is dispensable for virion assembly but is essential for lytic infection.PLoS Pathog.13, e1006455 (2017)..
Boigard, H. et al. Zika virus-like particle (VLP) based vaccine.PLoS Neglected Tropical Dis.11, e0005608 (2017)..
Sherman, K. E. et al. Zika virus replication and cytopathic effects in liver cells.PLoS ONE14, e0214016 (2019)..
Ronneberger, O., Fischer, P.&Brox, T. U-Net: convolutional networks for biomedical image segmentation.Proceedings of the 18th International Conference on Medical Image Computing and Computer-Assisted Intervention. 234–241. (Munich, Germany: Springer, 2015).
Selvaraju, R. R. et al. Grad-CAM: visual explanations from deep networks via gradient-based localization.Proceedings of 2017 IEEE International Conference on Computer Vision.618–626 (Venice, Italy: IEEE, 2017).
Vinogradova, K., Dibrov, A.&Myers, G: Towards Interpretable Semantic Segmentation via Gradient-Weighted Class Activation Mapping (Student Abstract).Proceedings of the AAAI Conference on Artificial Intelligence,34, 13943–13944. (New York, USA, 2020)..
Guzman, M. I. An overview of the effect of bioaerosol size in coronavirus disease 2019 transmission.Int. J. Health Plan. Manag.36, 257–266 (2021)..
Bake, B. et al. Exhaled particles and small airways.Respiratory Res.20, 8 (2019)..
Li, X. G. et al. Detecting SARS-CoV-2 in the breath of COVID-19 patients.Front. Med.8, 604392 (2021)..
Kingma, D. P.&Ba, J. L. Adam: a method for stochastic optimization. Preprint atarXiv: 1412.6980 (2014).
0
Views
0
Downloads
0
CSCD
Publicity Resources
Related Articles
Related Author
Related Institution
京公网安备11010802024621