The big problem with Operation Moonshot? False positives

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Back in April, the eminent cancer epidemiologist Julian Peto, a professor at the London School of Hygiene and Tropical Medicine (LSHTM), outlined a scheme for ending the UK lockdown which sent ripples through the medical community. Writing in the medical journal The Lancet, Peto proposed that the government invest in ramping up testing capabilities to the point where everyone in the UK would be tested for Covid-19 once a week, at an average of approximately ten million tests per day. He described this as a potential means to end the pandemic.
At the time, the idea was dismissed by other scientists as being practically and scientifically flawed. Peto’s colleague Liam Smeeth responded, “Is this a wise strategy and is it possible? We have absolutely no idea how testing ten million people per day in the UK could be implemented. Nothing on that scale has ever been attempted.”


But five months later, such a strategy is seemingly being pursued for real. On September 9, prime minister Boris Johnson announced the government’s landmark Operation Moonshot programme, which aims to deliver up to ten million tests a day – covering nearly a sixth of the entire population – and return results within as little as 20 minutes. Coming at a cost of a reported £100bn, just shy of the entire annual budget for the NHS, it has the twin aims of boosting economic activity, and avoiding a second national lockdown. But without better tests, it could end up creating more problems than it solves.
The reported plans are to roll out testing across various sites including workplaces, schools, entertainment and sporting venues, with regular tests prioritised for key workers, those in hospitals and care homes, ethnic minorities, teachers and shop assistants. The tests could also be linked to so-called “digital passports” that could allow people to access higher-risk events. In towns and cities where a spike in cases is identified, such as Leicester or Bolton, repeat testing of the entire population would be conducted until the virus was eliminated.
Operation Moonshot represents a vast expansion on the UK’s current testing program, which has come under heavy criticism in recent weeks for having inadequate capacity. Sarah-Jane Marsh, director of testing at NHS Test and Trace, admitted on Twitter that laboratory processing was a critical pinch-point. Right now, the UK is able to test approximately 350,000 people per day. Under the Moonshot timelines, this will rise to between two and four million by December, and then ten million by early 2021.
The government has stated that the onus will be on the private sector in order to achieve these milestones, with GSK responsible for supplying tests, Serco and G4S for logistics and warehousing, and AstraZeneca for laboratory capacity. However a quick glance across the English Channel illustrates that the logistical challenge is not so much achieving a set number of tests, but having the ability to process them all quickly.


As the threat of a second wave of Covid-19 grew last month, French health minister Olivier Véran promised that France would carry out one million tests per week by September 1. While this figure was met, the sudden rise in testing has overwhelmed lab capacities. “We’ve seen huge delays in the analysis of all the samples,” says Pascal Crépey, an epidemiologist at the Rennes School of Higher Public Health Studies. “It’s meant there have been delays of many days before people get the results back, which makes effective contact tracing impossible, and so this huge system becomes ineffective because in the end you can’t prevent all the chains of transmission. It’s an example of a situation where actually doing more tests ends up making the strategy less efficient.”
In an attempt to avoid similar problems – after all, the Moonshot targets would see the UK carrying out 60 times as many tests per week as France – the government is banking on a novel testing technology called Transcriptase Loop Amplification (LAMP). This is behind many of the new rapid tests currently in development, including those being developed by Oxford Nanopore, an Oxford University spinoff which signed a deal with the government in early August to deliver millions of tests in the coming months. LAMP is believed to be at least three times faster than the Polymerase Chain Reaction (PCR) tests – the current gold standard testing method – at detecting the SARS-CoV-2 virus genetic material in samples, raising the possibility that results could be delivered in under an hour.
The LAMP method is also thought to be capable of detecting traces of the virus in saliva. This would represent a much easier way of quickly sampling millions of people than the current swab tests which can be difficult and uncomfortable. However, scientists point out that there is currently no real-world evidence that any of these new tests could be effective at large scale sampling. While saliva tests were piloted on 10,000 people in Southampton over the summer, with further pilot studies set to be carried out in Salford, the results have yet to be made available.
“Rigorous evaluation of tests is essential,” says Angela Raffle, a consultant in public health from the University of Bristol. “We need to be sure that they deliver the best value in a real world setting not just under perfect laboratory conditions on a small number of ideal samples.”


However, Raffle and others are concerned about the government’s plans to use these tests to issue digital passports, stating that this is a misuse of their purpose. This is because LAMP and PCR tests can only detect the presence or absence of virus RNA in a sample, not whether they are actively infected and capable of spreading it.
“These tests aren’t screening tools because the RNA detected can be from live virus or viral debris from a recent past infection,” says Allyson Pollock, clinical professor of public health at Newcastle University. “Because of this, it doesn’t tell you whether the person who has tested positive has the virus or whether they’re at risk of infection.”
There is also the risk that the entire Operation Moonshot testing strategy could do more harm than good, simply because of the issue of false positives – people who erroneously test positive for the virus when they haven’t actually got it – which becomes a major problem when screening tens of millions of individuals every day.
Jon Deeks, professor of biostatistics at the University of Birmingham, points out that false positives are an unavoidable problem with any test. They occur because the detection threshold has to be highly sensitive in order to avoid missing the virus, but in the process the test will very occasionally pick up low levels of background contamination which are mistakenly classified as traces of SARS-CoV-2.
Normally false positives are not a big problem – the likely false positive rates of Covid-19 PCR tests have been estimated at 2.3 per cent, while the rate for LAMP is not yet known – but if ten million people are being tested every day, 2.3 per cent of cases can become a very large number, in the region of 230,000. “You’re talking about a number of people equivalent to the population of a small city having to isolate because of an erroneous result,” says Deeks. “And then when you think about all of the contacts of those people isolating too, it will soon cause far more economic harm than we’ve seen already. I’ve not heard of any other countries considering this. As Boris has noted, we’re out on our own with this, and some of us are saying there’s a good reason for that.”
Deeks estimates that the number of false positives returned by testing ten million a day would actually vastly outweigh the number of those who do actually have Covid-19, potentially of the order of 1000-1. This would lead to a need for even more testing, to try and validate whether people have Covid-19 or not.
Instead, he proposes that a more effective strategy would be to focus on making the existing testing and tracing system more efficient, while conducting targeted testing of symptomatic individuals and those in the highest risk groups. One of the most concerning aspects of France’s current testing backlog is that it is preventing the most vulnerable from being tested quickly enough, while 79 per cent of those turning up for tests do not have symptoms at all.
“We need to get the system working that we have already, because it isn’t working right now,” says Deeks. “So you get a test within 24 hours of needing it, and the result within 24 hours of that. And the contacts traced within 24 hours as well. If that was the speed we were working at, that would reduce transmission. And then thinking sequentially through various groups, from healthcare workers and home care workers, down to universities, and assessing the risk-benefit balance for conducting wider testing among those groups. Testing everybody could break the whole system very quickly.”
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