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DIAMONDS Project Using New Classification Approach to Develop Rapid Infectious Disease Tests

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NEW YORK – Investigators at Imperial College London are leading a project that could result in the development of multiple rapid diagnostics for detecting a spectrum of infectious diseases.

The team was awarded €22.5 ($24.9 million) in EU Horizon 2020 funding in January to pursue the project, called "Diagnosis and management of febrile illness using RNA personalized molecular signature diagnosis," or DIAMONDS. Technology partners on the study include BioMérieux and SkylineDx, as well as Imperial College London's biomedical electronics unit. The project will run through December 2024.

According to Michael Levin, a professor of professor of pediatrics and international child health at Imperial College, the aim of the study is to develop a library of genetic signatures for a variety of infectious and inflammatory diseases, and then to transfer these signatures over to a rapid test of about 100 to 150 genetic markers that can be administered at the point of care.

Rather than assessing a patient based on symptoms and then testing them for specific, suspected bacteria or viruses, such a test could determine the cause of a patient's disease based on a simple blood draw alone, he said. Potential diseases targeted by the test could include pneumonia, tuberculosis, sepsis, meningitis, and other inflammatory and immune diseases.

"We are identifying a new way of classifying disease," said Levin, who is the principal investigator on the DIAMONDS Project. "Until now, disease has been classified based on signs and symptoms," Levin said. "It's very much a clinician looking at the patient and using standard lab tests for blood chemistry and white cell count to guess what the patient has," he said. "Instead of this diagnostic process that follows a stepwise approach, we decided we could from the very first blood sample classify the patient and also develop a new molecular taxonomy of disease."

Such an approach could also help to reduce the overprescription of broad-spectrum antibiotics, as well as overcome current issues with detection approaches, as many clinicians still rely on culture, meaning that patients might have to wait one or two days to receive a specific diagnosis.

"There are huge numbers of children and adults in all parts of the world who are undergoing treatment with broad spectrum antibiotics because we have no rapid means of deciding whether they have a bacterial or viral infection or something else," noted Levin. He added that blood cultures are not only slow, they are also insensitive.

"Current diagnostic approaches to patients with suspected infections are both insensitive and slow," said Levin. "A huge proportion of resources are consumed on trying to pick out the needle in the haystack, the tiny amount of patients with a bacterial infection or something serious from a much larger group with viral infections who would get better on their own," he said. "The consequences of being unable to distinguish between the two is that a high amount of children treated with antibiotics are treated just because we suspect or fear they might have a bacterial infection when they probably just have a viral infection."

There are 27 partners on the DIAMONDS Project, most of them universities and hospitals in Europe, although the team does include institutions in Gambia, Nepal, and Taiwan. Reaching out to partners around the globe is based partly on the need to obtain enough samples to develop signatures for less common diseases, as well as to have access to more diverse samples.

"Any diagnostic test that is developed needs to also be tailored for Africa and Asia," said Levin.

Levin has led numerous EU-funded projects over the past 15 years that have allowed him and his team to amass genetic data on a variety of conditions, including tuberculosis and bacterial infections. According to Levin, this includes either microarray or RNA sequencing data on roughly 10,000 patients. For the DIAMONDS project, researchers will recruit another 5,000 patients who will undergo RNA sequencing.

"We hope to develop a European transcriptomic library of disease," Levin explained. "In this library, we will have the gene expression signatures of all the major classes of disease, bacterial, viral, inflammatory diseases and so on."

As the researchers work to develop their new molecular taxonomy of infectious and inflammatory diseases, which they call Personalized Molecular Signature Diagnosis, or PMSD, they are also engaging technology partners that will develop their vision into point-of-care tests.

According to Levin, the DIAMONDS Project is assessing several technologies for potential use in a large-scale pilot study across Europe in 2023 and 2024. These include BioMérieux's BioFire FilmArray Multiplex PCR System and a handheld platform developed internally at Imperial College. SkylineDx, a Rotterdam, Netherlands-based molecular diagnostics firm, which has developed array and next-generation sequencing based assays, is also a partner. Skyline's role in the project will be to define the criteria for the diagnostic platforms to achieve the desired healthcare outcomes using this approach.

Lacewing

Imperial College's diagnostic platform is called Lacewing and was developed by Pantelis Georgiou, a reader in biomedical electronics, and his multidisciplinary research team within the department of electrical and electronic engineering. This lab-on-a-chip device supports the identification of infections in real time, and reports the data to a cloud-based network, enabling public health surveillance and epidemiological investigations.

Each diagnostic test with Lacewing is run in a disposable cartridge, where targets are analyzed using over 4,000 arrayed chemical sensors integrated on a silicon microchip. Nucleic acid amplification is monitored in real time and the results are transferred via Bluetooth to an AndroidOS application run on a smartphone, where it is stored and processed.

"As a group, we are very focused on microelectronics, making microchips, and using them to create novel lab-on-a-chip devices," said Georgiou. "We have demonstrated that we can use ion-sensors to detect DNA by monitoring the release of protons during DNA amplification, which is a rapid and affordable alternative compared to gold standard qPCR instruments" he said. "Using that technique, we showed we could very reliably provide diagnosis at the point of care by creating a lab-on-a-chip technology able to identify pathogens, such as malaria or dengue in blood."

With Lacewing, Georgiou said that users should be able to obtain a diagnostic result within half an hour, though the group has achieved identification in less than seven minutes. In addition to speed, the group wants to reduce cost. Georgiou said that its target is about £10 ($13) per test for a panel of 12 markers. A corresponding real-time PCR test would cost about £60 in the UK, he said.

"So, it's a lot cheaper and offers clinical performance comparable to bench top instruments in the palm of your hand," said Georgiou.

Because there is a lot of demand for Lacewing from clinicians, such as Levin, Georgiou said the group wants to spin out the technology as a company, so that it can more easily produce the platform. "We need a proper supply chain. It's more difficult to do in a research lab." Eventually, he said, Lacewing could evolve into a diagnostics company.

And while technology partners in the DIAMONDS Project might be seen as jockeying for best performance with the best test eventually deployed in a European hospital context via the pilot study, he said it's possible that multiple platforms might ultimately be used.

"BioFire FilmArray is a bench top instrument," said Georgiou. "Ours is a handheld portable," he said. "We might see at the end there is room for both types of diagnostic approaches."

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