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3. Adding COVID-19 and other virus testing to your laboratory

Does using one method make the most sense, or will your lab turn to multiple methods for virus testing?

3.1 What methodologies will you use?

3.1.1 PCR

In the previous chapter, the most common testing methodologies for COVID-19 and other coronaviruses were discussed in detail. The prevailing method (often called the "gold standard") among them all was real-time reverse-transcription polymerase chain reaction (rRT-PCR) assays for testing. Broadly speaking, PCR is useful in pharmaceutical, biotechnology, and genetic engineering endeavors, as well as clinical diagnostics. As such, labs in those industries that already have PCR ifrastructure in place have a theoretical step-up over a lab that doesn't.

PCR technology has advanced to the point where it is more efficient and user-friendly than prior, yet "the high cost of the instruments, servicing contracts, and reagents pose major challenges for the market, especially to the price-sensitive academics."[1] Writing about the thirty-fifth anniversary of PCR in 2018, science writer Alan Dove not only highlighted these cost issues but also the size and energy requirments for running the equipment. "As a result, one of the defining techniques of modern molecular biology has remained stubbornly inaccessible to educators and unusable in many remote locations."[2] Various efforts have been made over the years to bring costs down by modifying how heating and temperature control are performed[3][4][5][6], but many of those system aren't typically optimal during a pandemic when turnaround time is critical.

Amidst the pandemic, additional challenges also exist to those wanting to conduct PCR testing for COVID-19 and other viruses. As was discussed at the end of the previous chapter, supplies of reagents and consumables are not particularly robust mid-pandemic, with shortages being reported since March 2020.[7][8][9][10][11][12][13][14][15] These shortages may eventually work themselves out, but they highlight the need for other varying methods that don't necessarily depend on the same reagents and consumables that are in short supply.

For those labs wishing to adopt PCR testing of viruses—particularly COVID-19—into their workflow while providing reasonable turnaround times, all is not lost. However, careful planning is required. For example, you'll want to keep in mind that some PCR machines require vendor-specific reagents. If you're going to acquire a particular instrument, you'll want to do due diligence by verifying not only the supported reagents but also those reagents' overall availability (real and projected). You'll also want to consider factors such as anticipated workload (tests per day), what your workflow will look like, and how to balance overall investent with the need for reasonable turnaround times.

As of August 2020, an increasing body of research is being produced suggesting ways to improve turnaround times with PCR testing for COVID-19, with many research efforts focusing on cutting out RNA extraction steps entirely. Alcoba-Florez et al. propose direct heating of the sample-containing nasopharyngeal swab at 70 °C for 10 minutes in place of RNA extraction.[16] Adams et al. have proposed an "adaptive PCR" method using a non-standard reagent mix that skips RNA extraction and can act "as a contingency for resource‐limited settings around the globe."[17][18] Wee et al. skip RNA extraction and nucleic acid purification by using a single-tube homogeneous reaction method run on a lightweight, portable thermocycler.[19][20] Other innovations include tweaking reagents and enzymes to work with one step, skipping the reverse transcription step,[21] and using saliva-based molecular testing that skips RNA extraction.[22]

3.1.2 Pooled testing

Another method some labs are taking to speed up turnaround time is using pooled testing. The general concept involves placing two or more test specimens together and testing the pool as one specimen. The most obvious adventage to this is that the process saves on reagents and other supplies, particularly when supply chains are disrupted. This methodology is best used "in situations where disease prevalence is low, since each negative pool test eliminates the need to individually test those specimens and maximizes the number of individuals who can be tested over a given amount of time."[23] However, it's best left to situations where expectations are that less than 10 percent of the population being tested is affected by what's being tested for.[23][24][25]

The downside of pooled testing comes with the issues of dillution, contamination, and populations with 10 or more percent infected. A target-positive specimen that comingles with other target-free specimens is itself diluted and in some cases may cause issues with the limit of detection for the assay. Additionally, if the pool tests positive, target-free specimens may become contaminated by a target-positive specimen. This may cause issues with any individual specimen assays that get ran. And the workflows involving pooling must be precise, as a technician working with multiple specimens at the same time increases the chance of lab errors.[23][24][25]Finally, at least in the U.S., an Food and Drug Administration (FDA) emergency use authorization (EUA) for a validated pooled testing method is required.[23] (Validation of pooled methods may differ in other countries.[24]) The U.S. Centers for Disease Control and Prevention (CDC) has published interim guidance on pooled testing strategies for SARS-CoV-2.

3.1.3 Rapid antigen testing

An antigen is a substance—often a protein but may also be an environmental like a virus—that provokes the immune system to produce an antibody against it.[26] As such, another approach to testing for the presence of a virus in a specimen is to test for the antigen rather than the antibody. An antigen test is useful as a repeated surveillance test, but it has drawbacks as a one-time diagnostic test.[27][28][29] For COVID-19 and other viral infections, an antigen test has the advantage that specimen collection can typically be done with a simple nasal swab rather than a more invasive nasopharyngeal swab. Another advantage, on one hand, is that antigen testing is more rapid and convenient because the extraction and amplification steps of PCR are not used. On the other, antigen testing is less sensitive for the same reason: you test only what's there (rather than amplifying the amount for greater sensitivity).[28][30]

A theory increasingly gaining traction, however, is that "[a] higher frequency of testing makes up for poor sensitivity.”[28][29][31] Several researchers have shared pre-print and published research suggesting this outcome[28]:

Larremore and his colleagues have modeled the benefits of more frequent tests, even ones that are less accurate than today’s. Fast tests repeated every three days, with isolation of people who test positive, prevents 88% of viral transmission compared with no tests; a more sensitive test used every two weeks reduced viral transmission by about 40%, they report in a 27 June preprint on medRxiv. Paltiel and his colleagues reached much the same conclusion when they modeled a variety of testing regimes aimed at safely reopening a 5000-student university. In a 31 July paper in JAMA Network Open, they found that, with 10 students infected at the start of the semester, a test that identified only 70% of positive cases, given to every student every two days, could limit the number of infections to 28 by the end of the semester. Screening every seven days allowed greater viral spread, with the model predicting 108 infections.

As such, the utility of antigen testing, despite its lower sensitivity, appears to be surveillance situations where a large group of individuals who are at risk can at regularly scheduled intervals of two to four days be screened. The end result, in theory, would be few people who are target-positive would be missed, positives could be isolated and verified with a more sensitive test, and more target-positive people would be identified and isolated before reaching peak infectivity.[28][15] To be clear, it's not a perfect solution, but as Harvard epidemioligist Michael Mina and Boston University economist Laurence Kotlikoff suggest, "[w]e need the best means of detecting and containing the virus, not a perfect test no one can use."[15] A coalition of six U.S. state governors has bought into that concept and agreed to work together with the Rockefeller Foundation, as well as the Quidel Corporation and Becton, Dickinson and Company, which have received FDA EUAs to market antigen tests for SARS-CoV-2.[31][14] However, it's not clear how those six states will best put the tests to use despite 1. their moderate sensitivity (and thus a greater chance of false negatives[31]) and 2. the question of whether or not the two companies can produce enough test kits for repeat testing in those states.[28]

3.1.4 LAMP and CRISPR

Early on in the pandemic, while PCR was getting most of the attention, reverse transcription loop-mediated isothermal amplification (RT-LAMP), an isothermal nucleic acid amplification technique that allows for RNA amplification, was also quietly being discussed[32][33], and it has since gained more attention.[34][35][36][37][38][39] The University of Oxford, for example, is in the process of getting a rapid, affordable, clinically-validated RT-LAMP test approved for the European market. Oxford also notes that "[a]n advantage of using LAMP technology is that it uses different reagents to most laboratory-based PCR tests."[39] Thi et al. have tested a two-color RT-LAMP assay with an N gene primer set and diagnostic validation using LAMP-sequencing, concluding that the pairing of the two "could offer scalable testing that would be difficult to achieve with conventional qRT-PCR based tests."[37] And California-based Color Genomics have set up their own proprietary RT-LAMP system, capable of handling up to 10,000 tests per day.[40]

In most cases, LAMP-based testing is much simpler than PCR, lacking the requirement of specialized instruments. Despite LAMP generally being thought of as less sensitive than PCR[30][40][41], the recent explosion of research into RT-LAMP methods for testing for the presence of SARS-CoV-2 seems to gradually indicate that "under optimized conditions," RT-LAMP methods may actually be able to rival the sensitivity and specificity of many RT-PCR COVID-19 test.[38] Esbin et al. add[38]:

These methods allow for faster amplification, less specialized equipment, and easy readout. LAMP methods also benefit from the ability to multiplex targets in a single reaction and can be combined with other isothermal methods, like [recombinase polymerase amplification] in the RAMP technique, to increase test accuracy even more. These techniques may be particularly useful for rapid, point-of-care diagnoses or for remote clinical testing without the need for laboratory equipment.

CRISPR methods are also being used in conjunction with RT-LAMP.[30][38][42] RT-LAMP creates complementary double-stranded DNA (cDNA) from specimen RNA and then copies (amplifies) it. Then CRISPR methods are used to detect a predefined coronavirus sequence (from a cleaved molecular marker) in the resulting amplified specimen. Though as of August 2020 approved assays using CRISPR-based detection of SARS-CoV-2 are limited to a handful of companies[30][43], the technology has some promise as an alternative testing method. It has the additional advantage of being readily couples with lateral flow assay technology to be deployed in the point-of-care (POC) setting.[38][43]

3.1.5 Point-of-care and other alternative testing

On August 5, 2020, the WHO published a draft blueprint for what they call Target Product Profiles (TPP), which "describe the desirable and minimally acceptable profiles" for four difference COVID-19 test categories.[44] Addressing POC testing, the WHO recommends that such assays[44][45]:

  • have a sensitivity (true positive rate) or at least 70 percent;
  • have a specificity (true negative rate) of at least 97 percent;
  • provide results in less than 40 minutes;
  • require diagnostic machines that cost less than $3,000 U.S.;
  • individually cost less than $20 for the patient;
  • be simple enough that only a few hours of training are required to run the test; and
  • operate reliably outside a clean laboratory environment.

While few of the available test systems can meet all these requirements, it's clear the push to expand COVID-19 testing to the point of care is accelerating.[45][46][46][47][48]

Examples include[49]:

  • a rapid breath test to detect volatile organic chemicals from the lungs;
  • an affordable, hand-held spectral imaging device to detect virus in blood or saliva in seconds;
  • an ultrahigh frequency spectroscopic scanning device to see virus particules resonating;
  • a method that combines optical devices and magnetic particles to detect virus RNA;
  • an RNA extraction protocol that uses magnetic bears;
  • the addtional use of an artificial intelligence (AI) application to better scrutenize test results; and
  • the miniaturization of PCR technology to make it more portable and user-friendly.

POLs:


3.2 What equipment and supplies will you need?

Instruments

Eppendorf Mastercycler Pro S, a thermal cycler for PCR and other applications

Thermal cyclers (a.k.a. PCR machines) - standard PCR systems, RT PCR - advantages of digital PCR systems such as precision, sensitivity, accuracy, reproducibility, direct quantification and multiplexing, and speed of the analysis systems, and digital PCR systems "The market is witnessing an emerging trend of digital and droplet digital PCR technology, which is sensitive and accurate than the traditional method."

https://www.thermofisher.com/search/browse/category/us/en/602552/PCR+Machines+%28Thermal+Cyclers%29+%26+Accessories https://blog.biomeme.com/how-do-you-test-for-covid-19


Reagents

template DNA, PCR primers and probes, dNTPs, PCR buffers, enzymes, and master mixes

Consumables

PCR tubes, plates, and other accessories https://www.sigmaaldrich.com/labware/labware-products.html?TablePage=9577275

Software and services

Vendors

Major players operating in the global PCR market are Bio-Rad Laboratories, Inc., QIAGEN N.V., F. Hoffmann-La Roche AG, Thermo Fisher Scientific, Inc. Becton, Dickinson and Company, Abbott, Siemens Healthcare GmbH (Siemens AG), bioMérieux SA, Danaher Corporation, and Agilent Technologies. Merck KGaA, Promega


References

  1. ↑ Kenneth Research (23 June 2020). "Polymerase Chain Reaction Market Sector Analysis Report, Regional Outlook & Competitive Share & Forecast - 2023". MarketWatch. https://www.marketwatch.com/press-release/polymerase-chain-reaction-market-sector-analysis-report-regional-outlook-competitive-share-forecast---2023-2020-06-23. Retrieved 06 August 2020. 
  2. ↑ Dove, A. (2018). "PCR: Thirty-five years and counting". Science 360 (6389): 670–672. doi:10.1126/science.360.6389.673-c. 
  3. ↑ Wong, G.; Wong, I. Chan, K. et al. (2015). "A Rapid and Low-Cost PCR Thermal Cycler for Low Resource Settings". PLoS One 10 (7): e0131701. doi:10.1371/journal.pone.0131701. 
  4. ↑ Kuznetsov, S.; Doonan, C.; Wilson, N. et al. (2015). "DIYbio Things: Open Source Biology Tools as Platforms for Hybrid Knowledge Production and Scientific Participation". Proceedings of the 33rd Annual ACM Conference on Human Factors in Computing Systems: 4065–68. doi:10.1145/2702123.2702235. 
  5. ↑ Norton, D. (11 May 2016). "Phila. med tech startup working on multimillion dollar government contract". Philadelphia Business Journal. https://www.bizjournals.com/philadelphia/news/2016/05/11/government-contract-biomeme-hiring-med-tech.html. Retrieved 06 August 2020. 
  6. ↑ An, J.; Jiang, Y.; Shi, B. et al. (2020). "Low-Cost Battery-Powered and User-Friendly Real-Time Quantitative PCR System for the Detection of Multigene". Micromachines 11: 435. doi:10.3390/mi11040435. 
  7. ↑ Herper, M.; Branswell, H. (10 March 2020). "Shortage of crucial chemicals creates new obstacle to U.S. coronavirus testing". STAT. https://www.statnews.com/2020/03/10/shortage-crucial-chemicals-us-coronavirus-testing/. Retrieved 10 April 2020. 
  8. ↑ Hale, C. (18 March 2020). "Qiagen aims to more than quadruple its COVID-19 reagent production in 6 weeks". Fierce Biotech. https://www.fiercebiotech.com/medtech/qiagen-aims-to-more-than-quadruple-its-covid-19-reagent-production-6-weeks. Retrieved 10 April 2020. 
  9. ↑ Mehta, A. (3 April 2020). "Mystery surrounds UK claim of Covid-19 test reagent ‘shortage’". Chemistry World. https://www.chemistryworld.com/mystery-surrounds-uk-claim-of-covid-19-test-reagent-shortage/4011457.article. Retrieved 10 April 2020. 
  10. ↑ Roche, B. (8 April 2020). "Irish scientists develop reagent in effort to ease Covid-19 testing delays". The Irish Times. https://www.irishtimes.com/news/science/irish-scientists-develop-reagent-in-effort-to-ease-covid-19-testing-delays-1.4223897. Retrieved 10 April 2020. 
  11. ↑ Padma, T.V. (13 May 2020). "Efforts to combat Covid-19 in India hit by imported reagent shortages". Chemistry World. https://www.chemistryworld.com/news/efforts-to-combat-covid-19-in-india-hit-by-imported-reagent-shortages/4011718.article#/. Retrieved 19 May 2020. 
  12. ↑ David, E.; Farber, S.E. (20 June 2020). "Survey shows resources for COVID-19 diagnostic testing still limited months later". ABC News. https://abcnews.go.com/Health/survey-shows-resources-covid-19-diagnostic-testing-limited/story?id=71341885. Retrieved 08 July 2020. 
  13. ↑ Johnson, K. (2 July 2020). "NC Labs Facing Shortages In COVID-19 Testing Chemicals". Patch. https://patch.com/north-carolina/charlotte/nc-labs-facing-shortages-covid-19-testing-chemicals. Retrieved 08 July 2020. 
  14. ↑ 14.0 14.1 Mervosh, S.; Fernandez, M. (4 August 2020). "‘It’s Like Having No Testing’: Coronavirus Test Results Are Still Delayed". The New York Times. https://www.nytimes.com/2020/08/04/us/virus-testing-delays.html. Retrieved 05 August 2020. 
  15. ↑ 15.0 15.1 15.2 Courage, K.H. (31 July 2020). "Should we be testing fewer people to stop the spread of Covid-19?". Vox. https://www.vox.com/2020/7/31/21336212/covid-19-test-results-delays. Retrieved 05 August 2020. 
  16. ↑ Alcoba-Florez, J.; González-Montelongo, R.; Íñigo-Campos, A.; García-Martínezde Artola, D.; Gil-Campesino, H.;
    The Microbiology Technical Support Team; Ciuffreda, L.; Valenzuela-Fernández, A.; Flores, C. (2020). "Fast SARS-CoV-2 detection by RT-qPCR in preheated nasopharyngeal swab samples". International Journal of Infectious Diseases 97: 66–68. doi:10.1016/j.ijid.2020.05.099.     
  17. ↑ Shapiro, M. (29 July 2020). "Streamlined diagnostic approach to COVID-19 can avoid potential testing logjam". Research News @ Vanderbilt. https://news.vanderbilt.edu/2020/07/29/streamlined-diagnostic-approach-to-covid-19-can-avoid-potential-testing-logjam/. Retrieved 06 August 2020. 
  18. ↑ Adams, N.M.; Leelawong, M.; Benton, A. et al. (2020). "COVID‐19 diagnostics for resource‐limited settings: Evaluation of “unextracted” qRT‐PCR". Journal of Medical Virology. doi:10.1002/jmv.26328. 
  19. ↑ Mehar, P. (27 July 2020). "Improving the speed of gold-standard COVID-19 diagnostic test". Tech Explorist. https://www.techexplorist.com/improving-speed-gold-standard-covid-19-diagnostic-test/34069/. Retrieved 06 August 2020. 
  20. ↑ Wee, S.K.; Sivalingam, S.P.; Yap, E.P.H. (2020). "Rapid Direct Nucleic Acid Amplification Test without RNA Extraction for SARS-CoV-2 Using a Portable PCR Thermocycler". Genes 11 (6): 664. doi:10.3390/genes11060664. 
  21. ↑ Council for Scientific and Industrial Research (30 July 2020). "Faster, local COVID-19 test kits could be ready by year-end". Engineering News. Creamer Media. https://www.engineeringnews.co.za/article/faster-local-covid-19-test-kits-could-be-ready-by-year-end-2020-07-30/. Retrieved 07 August 2020. 
  22. ↑ Ranoa, D.R.E.; Holland, R.L.; Alnaji, F.G. et al. (2020). "Saliva-Based Molecular Testing for SARS-CoV-2 that Bypasses RNA Extraction". bioRxiv. doi:10.1101/2020.06.18.159434. 
  23. ↑ 23.0 23.1 23.2 23.3 Rohde, R. (20 July 2020). "COVID-19 Pool Testing: Is It Time to Jump In?". American Society for Microbiology. https://asm.org/Articles/2020/July/COVID-19-Pool-Testing-Is-It-Time-to-Jump-In. Retrieved 06 August 2020. 
  24. ↑ 24.0 24.1 24.2 Masha, M.; Chau, S. (4 August 2020). "Pooled virus tests help stretched health services". Asia Times. https://asiatimes.com/2020/08/pooled-virus-tests-help-stretched-health-services/. Retrieved 06 August 2020. 
  25. ↑ 25.0 25.1 Citroner, G. (3 August 2020). "How Pooled Testing Can Help Us Fight Spread of COVID-19". Healthline. https://www.healthline.com/health-news/how-pooled-testing-can-help-us-fight-spread-of-covid-19. Retrieved 06 August 2020. 
  26. ↑ "Antigen". MedlinePlus. U.S. National Library of Medicine. https://medlineplus.gov/ency/article/002224.htm. Retrieved 07 August 2020. 
  27. ↑ Anderson, K. (6 August 2020). "5 Investigates: Concerns about current use of rapid antigen tests for COVID-19". WCVB 5 ABC. https://www.wcvb.com/article/5-investigates-concerns-about-current-use-of-rapid-antigen-tests-for-covid-19/33538332. Retrieved 07 August 2020. 
  28. ↑ 28.0 28.1 28.2 28.3 28.4 28.5 Service, R.F. (2020). "Radical shift in COVID-19 testing needed to reopen schools and businesses, researchers say". Science. doi:10.1126/science.abe1546. 
  29. ↑ 29.0 29.1 Kremer, R. (7 August 2020). "UW System Orders 350,000 COVID-19 Tests". Urban Milwaukee. https://urbanmilwaukee.com/2020/08/07/uw-system-orders-350000-covid-19-tests/. Retrieved 07 August 2020. 
  30. ↑ 30.0 30.1 30.2 30.3 Guglielmi, G. (2020). "The explosion of new coronavirus tests that could help to end the pandemic". Nature 583: 506–09. doi:10.1038/d41586-020-02140-8. 
  31. ↑ 31.0 31.1 31.2 Clark, C. (6 August 2020). "COVID Antigen Tests: Coming to Case Counts Near You?". MedPage Today. https://www.medpagetoday.com/infectiousdisease/covid19/87930. Retrieved 07 August 2020. 
  32. ↑ Lamb, L.E.; Barolone, S.N.; Ward, E. et al. (2020). "Rapid Detection of Novel Coronavirus (COVID-19) by Reverse Transcription-Loop-Mediated Isothermal Amplification". medRxiv. doi:10.1101/2020.02.19.20025155. 
  33. ↑ Schmid-Burgk, J.L.; Li, D.; Feldman, D. et al. (2020). "LAMP-Seq: Population-Scale COVID-19 Diagnostics Using Combinatorial Barcoding". bioRxiv. doi:10.1101/2020.04.06.025635. https://www.biorxiv.org/content/10.1101/2020.04.06.025635v2.article-info. 
  34. ↑ Yu, L.; Wu, S.; Hao, X. et al. (2020). "Rapid Detection of COVID-19 Coronavirus Using a Reverse Transcriptional Loop-Mediated Isothermal Amplification (RT-LAMP) Diagnostic Platform". Clinical Chemistry 66 (7): 975–77. doi:10.1093/clinchem/hvaa102. PMC PMC7188121. PMID 32315390. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188121. 
  35. ↑ Park, G.-S.; Ku, K.; Baek, S.-H. et al. (2020). "Development of Reverse Transcription Loop-Mediated Isothermal Amplification Assays Targeting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)". Journal of Molecular Diagnostics 22 (6): 729–35. doi:10.1016/j.jmoldx.2020.03.006. PMC PMC7144851. PMID 32276051. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144851. 
  36. ↑ Kellner, M.J.; Ross, J.J.; Schnabl, J. et al. (2020). "A rapid, highly sensitive and open-access SARS-CoV-2 detection assay for laboratory and home testing". bioRxiv. doi:10.1101/2020.06.23.166397. 
  37. ↑ 37.0 37.1 Thi, V.L.D.; Herbst, K.; Boerner, K. et al. (2020). "A colorimetric RT-LAMP assay and LAMP-sequencing for detecting SARS-CoV-2 RNA in clinical samples". Science Translational Medicine: eabc7075. doi:10.1126/scitranslmed.abc7075. PMID 32719001. 
  38. ↑ 38.0 38.1 38.2 38.3 38.4 Esbin, M.N.; Whitney, O.N.; Chong, S. et al. (2020). "Overcoming the bottleneck to widespread testing: a rapid review of nucleic acid testing approaches for COVID-19 detection". RNA 26 (7): 771–83. doi:10.1261/rna.076232.120. PMC PMC7297120. PMID 32358057. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297120. 
  39. ↑ 39.0 39.1 Hale, C. (9 July 2020). "Oxford researchers develop portable COVID-19 test costing less than $25". Fierce Biotech. https://www.fiercebiotech.com/medtech/oxford-researchers-develop-portable-covid-19-test-costing-less-than-25. Retrieved 07 August 2020. 
  40. ↑ 40.0 40.1 Sheridan, K. (6 August 2020). "This California company has a better version of a simpler, faster Covid-19 test". STAT. https://www.statnews.com/2020/08/06/better-simpler-faster-covid-19-test/. Retrieved 08 August 2020. 
  41. ↑ 41.0 41.1 Heidt, A. (9 July 2020). "Saliva Tests: How They Work and What They Bring to COVID-19". The Scientist. https://www.the-scientist.com/news-opinion/saliva-tests-how-they-work-and-what-they-bring-to-covid-19-67720. Retrieved 08 August 2020. 
  42. ↑ Broughton, J.P.; Deng, X.; Yu, G. et al. (2020). "CRISPR–Cas12-based detection of SARS-CoV-2". Nature Biotechnology 38: 870–74. doi:10.1038/s41587-020-0513-4. PMID 32300245. 
  43. ↑ 43.0 43.1 GlobalData Healthcare (14 July 2020). "CRISPR biotechnology set to disrupt Covid-19 testing market". Verdict Medical Devices. https://www.medicaldevice-network.com/comment/crispr-biotechnology-disrupt-covid-19-testing-market/. 
  44. ↑ 44.0 44.1 World Health Organization (5 August 2020). "COVID-19 Target product profiles for priority diagnostics to support response to the COVID-19 pandemic v.0.1". World Health Organization. https://www.who.int/publications/m/item/covid-19-target-product-profiles-for-priority-diagnostics-to-support-response-to-the-covid-19-pandemic-v.0.1. Retrieved 12 August 2020. 
  45. ↑ 45.0 45.1 Peplow, M. (10 August 2020). "Rapid COVID-19 testing breaks free from the lab". Chemical & Engineering News. https://cen.acs.org/analytical-chemistry/diagnostics/Rapid-COVID-19-testing-breaks/98/web/2020/08. Retrieved 12 August 2020. 
  46. ↑ 46.0 46.1 Krieger, L.M. (10 August 2020). "Coronavirus: How to test everyone, all the time". The Mercury News. https://www.mercurynews.com/2020/08/10/coronavirus-how-to-test-everyone-all-the-time/. Retrieved 12 August 2020. 
  47. ↑ Brown, D. (10 August 2020). "Point-of-care testing could be ‘biggest advance’ in COVID-19 fight". McKnight's. https://www.mcknights.com/news/point-of-care-testing-could-be-biggest-advance-in-covid-19-fight/. Retrieved 12 August 2020. 
  48. ↑ Wisson, J. (28 July 2020). "COVID-19 and effective cohorting: Rapid point of care triage testing". Health Europa. https://www.healtheuropa.eu/covid-19-and-effective-cohorting-rapid-point-of-care-triage-testing/101696/. Retrieved 12 August 2020. 
  49. ↑ Leichman, A.K. (27 July 2020). "10 ways Israeli scientists are improving corona testing". Isael21c. https://www.israel21c.org/how-israeli-scientists-are-improving-corona-testing/. Retrieved 11 August 2020. 
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