Method for developing diagnostic tests for future pandemics

Software that helps speed up the process of creating new diagnostic tests could help fight future pandemics, its developers say.

A team of bioengineers and chemists in Scotland and China have developed a system that suggests new reaction pathways to speed up the design and development of new diagnostic tests.

The system, which is now freely available for other researchers around the world to study, adapt and use, can also be used to identify early stages of non-infectious diseases like cancer, which could help patients get treatment faster.

In a new article published today in the journal Nature Communication, researchers from the University of Glasgow in the UK and Shanghai Jiao Tong University in China describe how they developed and demonstrated the effectiveness of their system.

They started by developing reaction graphs – representations of biomechanical processes that enable rapid diagnostic tests like cross-priming amplification (CPA) and DNA loop amplification (LAMP).

Unlike polymerase chain reaction, or PCR, tests that require access to sophisticated laboratories run by trained personnel, isothermal tests like LAMP can offer fast and accurate results by creating interactions between chemicals and DNA strands contained in patient samples, providing rapid results at the point of care.

However, in many cases these rapid tests are designed and developed for a specific purpose, which can introduce unnecessary complexity and make it difficult to easily adapt a test for a different diagnosis.

The researchers developed a more generalizable approach to creating new assays, by creating a software tool that could turn reaction graphs into suggestions for how primers and chemical reactions might be used to create desired diagnostic results.

In the paper, the research team describes how they probed the effectiveness of the software by using it to design the chemical primers and reactions for four different diagnostic tests – three for infectious diseases and one for cancer, a non-communicable disease.

They successfully created a multiplexed test for a form of HIV with high levels of sequence variation, a highly sensitive test for tuberculosis, and a study to analyze clinical patient samples for the presence of hepatitis B.

They also developed a test to detect short miRNA sequences relevant to the diagnosis and prognosis of cancers, including oral squamous cell carcinoma, breast cancer and glioma.

They used their newly designed diagnostic tests to test patient samples from clinical laboratories in China. Then they confirmed their results using separate PCR tests. They tested their results against LAMP diagnostics for the same diseases, finding that their results were more specific and reproducible than LAMP tests.

Professor Jon Cooper, James Watt School of Engineering, University of Glasgow, is the lead author of the paper. Professor Cooper said: “We have been working for several years to develop isothermal tests for diseases such as malaria and hepatitis C for use in parts of the world where reliable access to PCR testing is limited.

“During the construction of these diagnostic systems, it became clear that we were also figuring out how we could take a more generalizable approach to testing for specific biomarkers.

“Our programmable system automates much of the initial trial-and-error work that goes into developing new tests, and we have shown that it can be used to reliably diagnose a useful representative sample of communicable diseases and non-communicable.. This is an exciting discovery that suggests many potential applications in medicine.

Dr Julien Reboud, co-author of the University of Glasgow paper, added: “The COVID-19 pandemic has taught the world how vital it is to rapidly develop accurate, sensitive and specific diagnostics for track new diseases and direct treatment.

“Our programmable system offers a new avenue to support this type of rapid diagnostic development. We are keen to make it as accessible as possible to other researchers around the world, which is why we have made all of our graphics and data freely available online. We hope it will be of real use to researchers and clinicians in a wide range of applications, and we look forward to seeing what new applications they find for the system.

Dr Gaolin Xu, co-author of the paper based at Shanghai Jiao Tong University, added: “During my PhD. in Professor Cooper’s group, I developed new technologies for DNA detection. I’ve always believed there should be a better way to develop new diagnostic test designs. Upon my return to China, I continued to work with my Scottish colleagues to develop this exciting new diagnostic system.

The team’s paper, titled “Programmable Design of Isothermal Nucleic Acid Diagnostic Assays through Abstraction-based Models”, is published in Communication Nature.

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