Covid-19: what tests do we need?

My previous post summarised (*) the currently-used test for Covid-19, the PCR test, including its various limitations.

So what would improve it? Any new test would have to be:

*) Accurate. This means it would have as few false negatives and false positives as possible. Greater than 85% accuracy would be good. Chasing higher values (e.g. >95%) might delay the availability of tests, and allow the best to be the enemy of the good.

*) Sensitive. Sensitivity is the percentage of people with the disease that test positive. A patient may only have low amounts of virus in their system, especially early on, and therefore a test needs to be able to detect these low levels.

*) Selective. Selectivity is how well the test can separate the target disease (in this case Covid-19) from other, similar diseases.

*) Timely. Ideally, a patient or doctor would take a swab, and the result would come immediately, as it does with a pregnancy test or breathalyser. Any positives could then be taken through the existing PCR process for validation. Ideally, it would err towards false positives over false negatives.

*) Portable. Ideally it would be portable; the test can be conducted in hospitals, doctor's surgeries, or even in the home.

Various companies claim to be near this holy grail, and I hope they are correct. Ideally it would be multiple companies, allowing countries and organisations to choose which test - or tests - they believe are the best. South Korea have a rapid test that appears to be based on a speedier PCR process, but details on it appear to be sparse. However any PCR-based test will, by its very nature, be complex to administer.

Serological tests

Whilst PCR-style tests are useful, we also need other tests. The current PCR test only indicates if you have the disease; if you have had it, been symptomatic and beaten it, it will show up as a negative. Therefore we also need a serological test as well. This would show whether an individual has developed antibodies against this virus. Such a test could give us information on how prevalent Covid-19 has become in the community.

Serological tests are being developed by various groups. It appears that most will require a pinprick sample of blood, and the tests will be able to be performed in larger batches than PCR tests, easing restraints on laboratories. However the tests only work seven to fourteen days after the onset of symptoms, so there is still a need for PCR tests.

Many of the requirements for a PCR test are also required for a serological test: it will need to be sensitive, selective and timely.

For this reason, care needs taking that any newly-developed tests are actually fit for purpose, particularly in relation to false positives (in the case of antibody tests, false positives are more dangerous than false negatives. This is the opposite to PCR tests, where false negatives are the bigger problem).

There are other tests that might be useful, but the big two are the 'have-you-got-it-now' and the 'have-you-had-it' tests. Once we have these available in massive volumes, then we can start planning how to get back to normality. Without them, normality is a much rockier road.

Beware, the hustlers

Vast amounts of money will be available to anyone who manages to make a 'Holy Grail' test, and this will attract not only genuine actors, but charlatans. Some of these will be unknowing charlatans - people who genuinely believe 'their' solution is the Holy Grail when it isn't, whilst there will be genuine charlatans - snake-oil salesmen looking to make a quick buck. They will get discovered, but they could do massive damage in the meantime.

And before anyone thinks this doesn't happen, just remember James McCormick and the hideous ADE bomb-sniffer scandal (2). If people want something badly enough, others will sell them it - even if the item sold is worthless.

In addition, newly-developed tests would usually be run through trials to try to gauge accuracy, sensitivity and other values. The understandable hurry to get new tests out and used may lead to less understanding of the test itself, its limitations, and how it is to be administered.

A happier thought

It feels somewhat wrong - frivolous, perhaps - to say so, but this hideous disease has struck us at the best time in our history. We are not prepared, but we have the science and technology to fight it. We have a few decades of experience with genetic assaying as an invaluable tool in the battle, and we have had a few near misses in which we have developed basic tools. It can - and will be - argued that we should have done more after those near misses, but we're closer to winning the battle then we were.

Then there is another aspect: the Internet. Fifty years ago, the idea of essentially quarantining the entire country would have been unthinkable, from both an economic and social point of view. Now, the Internet allows us to communicate, order food, and in many cases even work from home. The Internet provides us with an invaluable tool in the battle - both economic and social.

(*) hopefully with a modicum of accuracy.

(1): https://wellcome.ac.uk/news/can-chloroquine-prevent-coronavirus-disease-only-research-will-give-us-answer
(2): https://en.wikipedia.org/wiki/ADE_651
(3): https://www.amazon.co.uk/gp/product/000728487X/

How do we test for Covid-19 ?

(Yet again, IANAE. Below is information I have gleaned from various sources for my own interest. Any mistakes are my own.)

In all the information being written about Covid-19, there seem to be few resources that highlight the test's methodology and its limitations. It has become a black box 'the test', and many - sadly including journalists - seem to be treating it as an all-conquering miracle.

In reality, whilst it's the best we've got, it's awkward.

The current Covid-19 tests have been produced very rapidly, and is a tribute to the companies and organisations that have developed them. They were aided by the fact there have been several close calls over the last couple of decades - for instance SARS in 2002 and MERS from 2012. These earlier diseases proved to be less susceptible to spreading between humans, and gave investigators a target to concentrate on. The Covid-19 tests are built on that earlier work, which is why we got test for Covid-19 within a couple of weeks of the outbreak starting.

The current commonly-used Covid-19 test are variants of a PCR test.

So (deep breath), what is a PCR test?

A polymerase chain reaction (PCR) test detects viral particles in bodily fluids, such as blood. It is essentially molecular photocopying: small amounts of a pathogen's DNA or RNA are copied many times (amplified) to a level where they can be detected. Without a PCR test, the virus's RNA would be at too low a level for detection. I like to think of it as a gigantic magnifying glass, although perhaps not wielded by Sherlock Holmes.

PCR's inventor, Kary B. Mullis, won a Nobel Prize for Chemistry it in 1993, and it initially proved useful for the Human Genone Mapping Project, although is also used for purposes such as DNA fingerprinting and genetic research (1).

So, what is the testing procedure?

1. A swab is taken from the patient, or a sample taken from the back of the throat.
2. The sample is sealed into a tube and sent to a lab for processing.
3. In the lab, the sample's RNA is extracted.
4. Chemicals are mixed with the sample in different combinations.
5. These mixtures are tested in a PCR machine.
6. The result is given as positive, negative, or uncertain (a catch-all for various errors and problems, for instance the presence of similar viruses).

There are many issues with the test:

• The PCR tests can only tell if you currently have the disease; not if you have had it and have recovered. For that, we need an antibody test.
• The test is not instant; samples have to be sent to labs (often distant) for testing.
• It is not just a case of having enough testing kits: you also need the downstream laboratory to process the samples. It is pointless having a test that you do not get a result from for weeks or months. Tales of countries or organisations ordering tens of thousands of kits seem to neglect the downstream processing. This processing means it is perfectly possible for (say) 10,000 tests to be performed in a day, but for results of only 8,000 to come through, as there is a lag between tests and results - especially if the labs are inundated with tests.
• The test takes time. Getting samples to a lab takes time. Extracting the RNA takes time. Mixing it with the chemicals takes time. Performing the PCR test itself takes time. Even when samples are batched up, it can tale many hours for a sample to be tested, and that does not include transport from patient to lab.
• The tests require consumables: from reagents to protective equipment for the lab workers. These consumables and workers are in short supply at a time when every country in the world is demanding them.
• The tests may be inaccurate. False positives (a patient reported to have the disease when they do not), is less important, as the patient will then be treated with caution, e.g. self-isolation. The big problem is with false negatives: where a patient is reported to be clear of the disease when, in fact, they have it. Some reports give the current test an accuracy of about 70%: in other words, it will only detect Covid-19 within a patient 70% of the time.

Why might false negatives be reported? (2)

1. In the early stages of the illness, the patient may have too low a viral load to be detected.
2. The swabs are taken from the nose and/or the back of the throat, and if the patient's respiratory illness is not too severe, not much of the virus may not make it up the respiratory tract.
3. The sample may be simply incorrectly taken.
4. The samples may have been poorly handled.
5. There might be technical issues in the test.

PCR is a tool, and as with any tool, it needs using with care, and with a deep understanding of the tool's limitations.

As an aside, PCR tests are used in Low Copy Number (LCN) DNA fingerprinting techniques, which allow tiny amounts of DNA to be fingerprinted in criminal cases. This is particularly useful in cold cases, where DNA might have degraded over time. The LCN technique proved somewhat controversial a little over a decade ago (3).

Hopefully we will get better, more immediate tests that do not require such a complex process. But in the meantime, thanks to all the companies, organisations and people who are working their socks off to increase the availability of testing kits and increase the testing capability.

(1): https://www.genome.gov/about-genomics/fact-sheets/Polymerase-Chain-Reaction-Fact-Sheet
(2): https://ourworldindata.org/covid-testing
(3): https://en.wikipedia.org/wiki/Low_copy_number#Criticism

Critical workers

Following on from yesterday's post, the government has published their list of critical workers on the gov.uk website:

https://www.gov.uk/government/publications/coronavirus-covid-19-maintaining-educational-provision/guidance-for-schools-colleges-and-local-authorities-on-maintaining-educational-provision

So, how did I do? I think fairly well. I missed off police (annoyingly, as I had them on my written list), and totally missed off prison officers, and the military.

In fact, the list is broader than I expected, with categories like 'essential financial services provision'.

I'd also hope that companies can apply for exemptions for their staff, e.g. if a company is working making ventilators (or components thereof), or scientists working on vaccines and tests, or companies making tests.

All in all, I think it's a good, comprehensive list. I wonder how many people it covers? Five to ten million, at a guess.

What is a 'critical worker' ?

With the shutdown caused by Covid-19 slowly rushing towards us like a particularly laggardly iceberg, it has been announced that special measures are being put in place to help 'critical workers' - such as creche schools for their children allowing them to still go to work.

This leads to a question: what is a 'critical worker' ?

Firstly, it probably depends from crisis to crisis: in a war situation, anything to do with the military, logistics, and wartime production would be critical.

But we are facing a health emergency, and therefore doctors, nurses, and all the frontline staff are undoubtedly critical.

In trying to work out how we as a family will cope with an extended stay in our home, I made two assumptions:
1) We will continue having power (i.e. gas, electricity).
2) Water / sewage will not be interrupted.

In my view, both of these are critical. A population left without power, water or sanitation for any length of time will soon see deaths occurring regardless of Covid-19. People need power, even in the milder weather of a UK spring. Much food will be frozen, and all that dried pasta needs cooking. And to ensure these services, people need to be working on maintaining them. If not serviced, things break. And when things break anyway, we need people to fix them.

Then there is telecoms. We are being told to work from home where possible, and it can be argued that this is not critical. However people rely on the Internet nowadays, and being able to keep in contact with family and friends far away will be a boon, and in many cases a lifesaver. Your elderly friend has run out of food? With communications, you have a hope of getting some to her. Likewise, our son's school is understandably leaning heavily on online resources to teach during this extended break. And the Internet could be a great morale raiser to people trapped in their homes.

Another example: food and logistics. Many people I know are relying on online grocery deliveries for their food. This has meant they have done little or no hoarding, and will rely on as much of their deliveries making it through as possible. This is probably a good, centralised way of restricting social contact. If this was to be a prolonged situation, you could use logistics and central distribution instead  to 'fairly' dole out essentials rather than ration cards, although that's admittedly a very rocky road.

Finally, there is what I would call the essential support staff - a good example in this crisis being the teachers who will look after the children of all the critical workers.

So, I'd create a rank of essential services for this outbreak:
1) Medical and related.
2) Essential services (gas, electric, water, sewage)
3) Logistics / deliveries
4) Telecoms
5) Assorted support (e.g. teachers, planners, decision makers)

I am almost certainly missing some. for instance, how long can society last without bins being emptied? For individual households, that might be less problematic. For many communal spaces, it might be. How about postal services (i.e. Royal Mail) ?

It will be interesting to see what the government comes up with later.

 Any thoughts?

Okay, I thought I'd put my tuppence forwards on the current Covid-19 crisis, and the decisions that the government have to make. I am not an expert; I have no particular knowledge on medical matters or pandemics - so I'm in the same boat as most of us!

Feel free to disagree, but these are my current thoughts, and please forgive the length:

1) We are working on incomplete data, and are having to make decisions based on assumptions. This is always risky. Just a relatively small change in one piece of data might invalidate one approach, whilst validating another. For instance, if a working vaccine is not developed before the end of the year, then isolating everyone now becomes a less valid approach. If a working vaccine is developed by mid-year, then isolating everyone now makes more sense.

Likewise, the number of asymptomatic cases (that means, the people who get Covid and are not recognised as such because they don't get major symptoms) is important. As we don't have a reliable mass antibody test yet, this is a major unknown that again has a major effect on the decision made. If there are a small percentage of asymptomatic cases, then isolating now makes more sense than if there is a high percentage.

Experts and politicians can look at the data and come up with different conclusions. Reasonable people can reasonably differ, especially in the presence of uncertain data.

2) Every country is different: in their stage of the epidemic, the way it is progressing, and in their social mores. In some countries, the epidemic is in only one or two regions, and therefore the rules applied to those regions can be specialised. Here in the UK, we do not have particular hotspots, and no reason to believe it can be contained in particular areas or regions of the country. Likewise, we do not live in a state where (allegedly) doors to apartments can be welded shut to keep them from leaving. We appear to be a week or two behind other countries in the outbreak; what works for them now might not work for us, now; it (or another approach) may work for us in a week.

Blindly comparing our decisions to those of other countries without factoring in such differences is, at best, pointless. This is not about some Union Jack-waving British exceptionalism; it's about the reality that our situation differs - as does every country's.

3) There might not be a 'right' way to handle this. There is a good chance that no approach is perfect, and that even when the current situation has died down, we won't know what the 'right' thing to do was. We are living through a massive experiment.

4) What is 'obvious' is often non-obvious. A common call is for schools to be closed, as has been done in other countries. Yet that can have side effects: children (who, unlike the 1918 flu pandemic, appear to be least affected by the illness) have to be cared for, and that burden will often fall on grandparents - who are most affected. Likewise, Madrid has had to lock shut the gates to playgrounds, as children were just meeting up there instead. What happens with exams? Coursework? A 'simple' decision has massive consequences - and not all in one direction.

5) I'm very glad I'm not the one who has to make these decisions.

In the UK's case, I don't see any reason to believe that Boris Johnson, the government, the Chief Medical Officer, the Chief Science Adviser et al *want* this awful disease to spread and for lots of people to die. They're having to use incomplete data to come to a decision in a terrible situation. I hope they've made a good one.

6) Finally: much of this is up to individuals. If you want to keep you and yours well, don't be silly, and follow the advice. Bulk-buying toilet roll is of little use. Wash your hands. Avoid touching your face. If you feel unwell, rest and isolate yourself as much as possible.

Help your relatives. Help your friends. Help your neighbours.

Chris Packham

Apparently Chris Packham is launching a judicial review of HS2, saying it does not take carbon emission targets into account.

https://www.bbc.co.uk/news/business-51722251

Which I found slightly odd, because a little blip in my memory recalled something. So I look on his website, and find nothing under the 'travel' link:
https://www.chrispackham.co.uk/category/travel-with-chris-packham

However the wonderful Wayback machine shows the following:
https://web.archive.org/web/20191214183301/https://www.chrispackham.co.uk/category/travel-with-chris-packham

So Chris Packham feels it's perfectly fine to make money out of taking adoring fans on trips to Alaska, Antarctica, the Gambia, Kenya etc - which of course involve environmentally-harmful flights  to and from the ships or locations - but does not want the hoi polloi in the UK to be able to travel.

He also says 'Bakotu Hotel – the base for my first tour – is my second home.' How nice it must be for him to have a second home in the Gambia. I bet he walks there ...

RED month, July 2019

On July 1st, I set out to do an early morning run. A task I repeated the next day, and the next. This morning I completed my 31st run of July, and I had Run Every Day.

So, the stats: I ran 176 miles in the month, or an average of 5.89 miles per day (and yes, I wish I could have made that up to a round 6). I spent a smidgen under 32 hours running, and ran at a rather pedestrian 5.5 MPH average (more of a jog, really). My total ascent was 488 metres - a consequence of living in rather flat Cambridgeshire. My earliest start time was 04.20, my latest 09.20. All bar three runs were started before six in the morning, so I could get home and showered before Sencan left for work.

The most I'd ever run before was 10K runs on 10 consecutive days, so it feels good to have somewhat smashed that. I exceeded my target distance on every run.

The lessons are numerous. After about the fifth day, I gave up on trying to go fast, as it only meant I'd go slower the next day. Recovery time is important for speed, and running every day does not allow for recovery time. I hate doing stretches. Running in light rain in summer is very pleasant. Seeing the sun rise is always uplifting. Running up slight gradients is wonderful. A 15km (9 mile) run is harder than a 20-mile walk with backpack. Running sans shirt is wonderful in warm weather, although alarming for anyone who sees a hairy bear running towards them!

I have suffered some chaffing on my inner thighs and, rather embarrassingly for a man, one sore nipple that was cured by liberal applications of vaseline that caused my running shirt to appear as though I was lactating. My knees are surprisingly fine, and my bad ankle only gave me trouble on a couple of occasions. I am very tired, but have lost over 5kg in weight.

The worst thing is:

I hate running!

And I shall get up tomorrow and run again. But I might take a day off after that. Or not ...