Health & medicine Science & tech

True positives

When they work, Covid tests are good for one yes or no question. If only it were that simple to work out how to use them. Repeatedly, mass testing programmes have foundered on the risks of false negatives, but how else can we live with the virus? And what kind of role might be played by AI screening tools, wearables and CRISPR-based technologies? Abi Millar speaks to developers and researchers to find out.

As the Covid-19 vaccination rollout continues, many countries remain stuck in what feels like indefinite lockdown. Restrictions are poised to continue, in most places, until some critical threshold of immunisation has been reached – with bars, restaurants, and even workplaces stubbornly out of bounds, and population-wide curfews in place.

Austria, however, has hit on a different solution. The small European nation, which suffered particularly badly in the second wave, is banking on extensive Covid-19 testing as the best way to reopen public life. It has said it will make 3.5m free Covid tests available to its 8.8m citizens each week – meaning you could get your hair cut or visit a ski resort, on the proviso you had a recent negative test.

Supposedly, testing everyone at a school or workplace would catch any pockets of infection and stop outbreaks in their track. It would also enable everyone who tested negative to go about their lives almost normally, reducing the disastrous social and economic consequences of prolonged lockdowns.

“We are on the way to becoming the testing world champion,” said the Austrian chancellor Sebastian Kurz. “Our goal is to be able to control the incidence of infection, or at least mitigate any growth in infection numbers, as best we can, by testing as much as possible.”

Austria isn’t the first country to think along these lines. In June 2020, China completed a mass testing programme in Wuhan, the centre of the original Covid outbreak. Almost 11 million people were tested, with the very few positive cases isolated and their contacts traced.

Then, in October 2020, Slovakia followed suit, testing 3.6 million people (97% of the eligible population) over the course of a single weekend. Those testing positive (around 38,000 people) were asked to quarantine along with their households, while the rest retained their freedom of movement and were able to go to work.

Smaller-scale testing programmes are now being rolled out elsewhere. In England, the government is counting on mass testing as a way to get children safely back into face-to-face education. From 8th March, schoolchildren have been getting tested twice a week. This mirrors similar programmes in Cyprus, which has also rolled out testing in workplaces, Germany, which now entitles each person to a weekly test.

The downsides of mass testing programmes

Unfortunately, mass testing programmes – particularly when you’re screening for asymptomatic Covid – remain an article of some controversy. Questions have been raised about the reliability of the tests, which come with a significant risk of false positives and false negatives. A false positive would mean you and your household are forced to self-isolate, potentially losing income, in the absence of any real infection. A false negative might embolden you to act as if you didn’t have Covid when in fact you were at risk of spreading it.

England’s school testing programme relies on controversial lateral flow tests, designed by Innova, which are cheap and can return results in 30 minutes. These tests have only moderate sensitivity and aren’t very good at picking up asymptomatic infection.

When the tests were trialed in a community pilot study in Liverpool, 60% of infected symptomless people went undetected, including a third of those with high viral loads who were at risk of infecting others. Doubts have been raised at how effective they will be at suppressing infection in schools.

Slovakia also used lateral flow tests, this time designed by Roche / SD Biosensor. The initiative is thought to have cut infection rates by around 60% in the absence of a strict lockdown. Unfortunately, this was not enough to prevent the emergence of a devastating third wave, with the country reporting one of the highest per capita death rates in the world by February.

It is clear that if mass testing programmes are ever going to fulfill their purpose, two conditions need to be satisfied. First, testing cannot be the only thing a country is doing to suppress the virus. Second, the tests need to reach at least some minimum threshold of accuracy coupled with affordability – which may mean thinking beyond lateral flow tests and PCR.

“PCR tests costs $100 in the US,” points out Niraj Jha, co-founder of the artificial intelligence company NeuTigers. “If we go with PCR and there are eight billion of us on this this planet and we test every day, that would cost $800bn every day so that the economy can open up. It isn’t feasible.”

He is referring to polymerase chain reaction (PCR) tests, which have a sensitivity and specificity of more than 95% and are regarded as the ‘gold standard’ of Covid-19 testing. While suitable for testing those with symptoms, they require specialist lab equipment, and are therefore too expensive, slow and costly to be deployed in a mass-screening approach.

Improving triage at venues

Jha’s hope is that his company’s new rapid screening app, CovidDeep, could provide an alternative. The app, which uses biometric data, could be used to triage those who need a PCR test. NeuTigers says it is more than 90% accurate in predicting whether a person is virus positive or virus negative – nearly twice as effective as current triage tools like temperature checks and questionnaires.

In conjunction with wearable devices, the app collects data like blood pressure, blood oxygen levels and skin temperature, and checks these against the telltale markers of Covid-19. During the app’s development process, the company collected hundreds of thousands of data points from research participants. It then used neural networks to learn how the virus affected these metrics. The algorithm can spot physiological patterns of Covid even in those who don’t perceive themselves as having symptoms.

“To manage the pandemic while going to work and leading a normal life, we need to get tested every day, but with current technologies that isn’t possible,” says Jha. “CovidDeep requires only two minutes of data collection and is accurate. It opens up the possibility we can tackle the pandemic and open up the economy at the same time.”

CovidDeep might be a useful solution for those who want to test themselves regularly in a non-invasive way. However, users would need to buy an EmpaticaE4 wristband as well an off-the-shelf device that can measure blood pressure and blood oxygen readings. Arguably, few individuals would be willing to shoulder this cost, and the app may be better suited to venues that need to test multiple people as a condition of entry. NeuTigers says the app is being adapted to work with connected consumer health products from Fitbit, Apple and others.

Allocating PCR tests to the right people

CovidDeep is not the only AI-based tool in development. AI-COVID, designed by Biocognitiv, could be used as a triage tool in hospitals. It uses physiological data taken from Complete Blood Count and Complete Metabolic Panels – common, cheap lab tests ordered by emergency departments in the US – and assesses markers of infection like blood clotting and inflammation. The tool generates results almost instantly and can be run on top of the blood tests for minimal added cost.

The tool has a very high sensitivity of 95%, along with moderate specificity of 49%. This means it can identify Covid-negative patients with high accuracy, allowing hospitals to allocate PCR tests to the patients most likely to need one. It was tested in collaboration with researchers at the University of Vermont and Cedars-Sinai, who are thrilled at its potential.

“We took everyone who’d had a PCR test for COVID, regardless if it was positive or negative, and had also had all these routine blood tests, and we told the computer to find patterns,” says Dr Timothy Plante, lead study author and assistant professor at the University of Vermont. “It came out with this tool that was almost too good to believe. The performance of this tool is far above and beyond what we’re used to in epidemiology.”

He is excited about the prospects of AI-COVID, not just as a predictive tool for Covid-19, but as an example of the kind of technology that may soon be ubiquitous in medicine.

“The complexity that computers can assess is far and beyond the complexity that we can see as humans,” he says. “Computers can assess really subtle patterns that correspond with certain outcomes. So that is to say that AI has yet to have its heyday in medicine. It’s in the future, and it’ll help with complex decision making down the road.”

CRISPR-based diagnostics

Another technology being hyped for Covid-19 testing is CRISPR, the gene-editing tool. Several companies are developing CRISPR-based tests that can be used to detect viral RNA in a sample.

Dr Melanie Ott, director of the Gladstone Institute of Virology, is developing one such test together with colleagues at UC Berkeley. In proof of concept studies, it has been able to return results within five minutes using a simple smartphone based device. While not currently as sensitive as PCR, it is suitable for use at the point of care, and is even able to quantify the person’s viral load.

“Part of breaking the pandemic is going to be identifying and isolating people who are infectious very early, so that they cannot spread the virus,” says Ott. “It’s in that rapid testing role that we see our biggest advantage. That’s also where I think knowing whether your viral load is going up or down could be very important, because you’ll know whether you’re going into an infection, or whether you’re at the tail end of an infection.”

Although the device is not yet at the point of commercialisation, Ott hopes it could one day be used in doctors’ surgeries, small business, pharmacies, airports and students’ dormitories.

“When it comes to clinical diagnostics, where you want to pick up the last bit of RNA that you can find in a nasal sample, I think PCR will potentially stay the standard,” says Ott. “But when it comes to rapid, inexpensive, deployable testing – and also when you want to quantify the virus – I think CRISPR could replace the PCR. It’s a very good supplement.”

Clearly, none of these technologies amounts to a magic bullet for ridding the world of Covid-19. However, over the months ahead we may start to break the stranglehold of PCR and lateral flow tests, with a variety of different triage and testing tools to choose from. Factor in the rollout of vaccine programmes, and it’s easy to imagine a future in which these technologies play a role in helping us all stay much safer. Time – and the experiments in Austria and elsewhere – will tell.

This article appears in the 2021 vol 1 edition of Practical Patient Care

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