Posts from March 2020 (16)

• An opinion poll on the NZ lockdown, at the Spinoff.  This is notable for being a self-selected online sample, but not a bogus poll — it’s properly reweighted to population totals for age, gender, and region, and this week being on Facebook or Instagram is probably more representative than answering your phone.  Interestingly, 9% of people say they won’t obey the rules, but only  7% say the rules shouldn’t be enforced.
• XKCD has a … unique  … way to describe the 2m distancing zone.
• Tableau have graphs of population mobility across the US, purporting to measure the success of social distancing. But they didn’t take interstate highways (where people tend to move rather a lot) into account
• A good graph of case age distributions in NZ — answering the basic statistical question ‘compared to what’?
  
• A terrible pie chart from ABC news in the US, via several people: these aren’t things that add up
  
• And from Macleans.ca: rates per 100k population don’t add up either — Yukon, Nunavut, and the  Northwest Territories have not actually done a third of Canada’s testing
  
• On the other hand, this graph of unemployment claims from the New York Times is spectacular.  Depressing, but spectacular.
  

“Doctors can now prescribe chloroquine for that off-label purpose of dealing with the symptoms of coronavirus,” Pence said. “The president’s very optimistic.”

Since clinical trial design and analysis is a thing I do, I thought I’d write about the chloroquine problem.

Chloroquine and the related hydroxychloroquine are anti-malarial drugs, which are also used in some autoimmune diseases.  They are inexpensive and their risks are well understood, with chloroquine having been used to prevent and treat malaria for many years.  They’re safe-ish at the standard doses^*: they have unpleasant side-effects, but not nearly as unpleasant as malaria.  Also, they’ve been found to have anti-viral effects in lab studies, including against SARS, so they might just work in treatment or prevention of COVID-19.

You might wonder how a malaria drug would work on a virus.  I will quote a pharmaceutical chemist, Derek Lowe

So if you see someone confidently explaining just how chloroquine exerts whatever antiviral activity it may have, feel free to go read something else. No one’s sure yet.

Now, you wouldn’t expect the President of the United States to be up on candidate antiviral treatments for SARS, so why was he very optimistic?

A small study in France gave hydroxychloroquine to 26 people with COVID-19, and didn’t give it to 16 others — this wasn’t randomised, it’s just how things turned out.  Of the 26 people getting hydroxychloroquine, 14 were virus-free after 6 days. The study reported this as 70%, because 6 of the other 12 people had dropped out for various reasons, including one death.   Normally, you’d report it as 14/26, or 54% — either that or do some more complicated analyses.   A subset of at least 6 of the people getting hydroxychloroquine also got the antibiotic azithromycin (they don’t say how many — could be anything from 6 to 12). Of these people, 6 became virus-free, which they reported as 100%.

This study is encouraging, but the fact that it’s not randomised and is very small and didn’t report results for nearly a quarter of the treated people mean that it’s no more than that. It’s a good reason to do a randomised trial that’s large enough and well-designed enough to convince people which ever way it turns out. That’s happening: the WHO is running a trial of four potential treatments, which is designed to be simple enough that even an over-worked and under-resourced hospital system can take part.  The trial design also allows for changes if new treatments or new information about existing treatments emerges.

As I’ve mentioned before, there are lots of small studies being done around the world.  In particular, the Journal of Zhejiang University just published a small randomised trial of hydroxychloroquine.  I learned about it from Dr Mel Thompson, who was quoted in a Forbes post about the trial, by Tara Haelle.  In this study 15 people were given hydroxychloroquine and 15 got the standard care.  This trial is too small to say much, 13 of the treated group and 14 of the control group were virus-free after 7 days, and the results for other measurements were also not too different.   The trial results are consistent with the drug having no effect. But they’re also consistent with the drug having a big effect.

At the moment, some people are getting various treatments and others aren’t, mostly in a haphazard way.  If it were done with randomisation and reliable basic data collection, we might save a lot of lives. At worst, we’d know what didn’t work.

^* Yes, one person died and one was hospitalised in the US from taking chloroquine, but they don’t seem to have known anything about the usual doses, which matters when the fish-tank version of the product comes in large packets.

“The” mortality rate isn’t a thing.

We know that older people are more likely to die than younger people — age is routinely and accurately recorded by hospitals, so the comparisons are relatively straightforward.  There’s less evidence for other general health risk factors, but there’s definitely some, and less healthy people are more likely to die.  Also, if there’s any point to our concern about running out of intensive care beds, then ICU treatment makes a different to the death rate.  It’s quite likely that there are other environmental factors, such as the types of bacteria that are around to cause secondary infections.

All this is hard to be sure about, but at least we should be interested in age-specific rates, either on their own or combined into an age-standardised rate.  David Spiegelhalter (statistician, risk communication expert from Cambridge) used estimates from the UK epidemic modellers(PDF) at Imperial College to draw this graph. The estimates attempt to model both the detection/testing rate and the fact that some people in the data set were still sick. There’s still uncertainty as to the absolute level, but the estimates are reasonable

Ordinary all-cause mortality increases with age, and apart from the infant spike and the young-and-stupid bump in the usual death rates it matches the COVID-19 pattern remarkably well.

Different people will draw different messages from this (the data never speak for themselves), but I think it supports the revised message  around severity for younger adults.  If you’re young and healthy, you are very likely to survive COVID-19 — but part of that is because you’re hard to kill, not because it’s a minor illness.  Think of it as like a car crash that would kill a 75 year old but might just give a 25 year old a week in hospital and a few months’ painful recovery.

Obviously this week is different in a number of ways. Empty stadiums, Warriors with a depleted squad. My predictions take no account of these changed circumstances.

Team Ratings for Round 2

The basic method is described on my Department home page.
Here are the team ratings prior to this week’s games, along with the ratings at the start of the season.

Performance So Far

So far there have been 8 matches played, 6 of which were correctly predicted, a success rate of 75%.
Here are the predictions for last week’s games.

Predictions for Round 2

Here are the predictions for Round 2. The prediction is my estimated expected points difference with a positive margin being a win to the home team, and a negative margin a win to the away team.

One of the problems with reporting of clinical trials is failure to distinguish “we showed this treatment doesn’t work” from “we didn’t show this treatment worked”.  In both cases, what people mean is that their uncertainty interval included “no benefit”, but it matters what other possibilities are in the interval.

A clinical trial in COVID-19 has just reported in the New England Journal of Medicine, testing the HIV drug lopinavir, which showed some lab evidence of being able to block the replication of SARS-CoV-2, the COVID-19 virus.  The great advantage of lopinavir is that we’re already manufacturing and distributing lots of it, in many countries, so if it worked, it could fairly easily be made available.

The trial reported

In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care.

It’s natural to interpret this as “it doesn’t work”, but it’s not really accurate.  The mortality results are given as

Mortality at 28 days was similar in the lopinavir–ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7)

Now, that’s very weak evidence of a benefit, but the interval goes from a massive 17 percentage point reduction to 6 percentage point increase in mortality.  The data are slightly closer to a 10 percentage point reduction in mortality than to no effect. The trial is just too small to tell us the answer.  Personally, I don’t expect lopinavir to work, based on what I’ve read from medical chemists who don’t think the lab motivation was compelling, but either way this trial isn’t decisive.

In ordinary times a undersized trial like this shouldn’t be done, and while it might still be done, it wouldn’t end up in the world’s highest-impact medical journal.  In the current circumstances there will be a whole bunch of undersized trials being run, and providing really valuable information, and we want them all to be published and combined.  And not overinterpreted.

• Statisticians from the Human Rights Data Analysis Group write in the UK literary magazine Granta, about the uncertainty in COVID-19 mortality rates.  They’re saying similar things to what I and other statisticians have said, but should be reaching a new audience, including some influential people.
• The infectious disease modelling group at Imperial College, London, have put out a new paper on suppressing infections (PDF, Financial Times, Guardian).  The take-home message is the same as the animation in this Spinoff piece by Siouxsie Wiles and Toby Morris: distancing measures can potentially suppress the epidemic, but if they work we need to keep doing them until a vaccine arrives. “The major challenge of suppression is that this type of intensive intervention package – or something equivalently effective at reducing transmission – will need to be maintained until a vaccine becomes available (potentially 18 months or more) – given that we predict that transmission will quickly rebound if interventions are relaxed”
• Alberto Cairo links to an interesting essay (previously a lecture,PDF) on ‘the ethics of counting’: “But wait!” the kid thinks to himself. “A grown-up lumped these different things together so I guess I’m supposed to consider them as the same.” Notice that when kids learn to count, they’re not just learning number words and symbols; they’re learning how adults see things
• Via flowingdata.com, a map of all the trees and forests in the United States
• From Kieran Healy, a map of all the rivers and streams in the US
• Along similar lines, from the Herald a couple of years ago, a map of NZ with place names coloured by whether they are in te reo.

You can divide most of the coronavirus stories in the world media into two groups: accurate and helpful information on the one hand, and harmful misinformation on the other.  The NZ media have been doing pretty well in keeping to the first sort.

There are a few stories in the middle, like this one at Newshub, that seem to be intended mostly as entertainment

Some people are making sure they will enjoy their time in quarantine, should it be enforced upon us. 

New Zealand sex retailer Adult Toy Megastore has reported a surge of sales in lubricant, vibrators and batteries in the wake of the pandemic. 

They don’t sell toilet paper or bottled water, so they’re bound to have somewhat different top products from the supermarkets, and there’s nothing really surprising here. In contrast to the previous StatsChat appearances of this store, they’re sticking to topics where they actually know the data, rather than overinterpreting bogus surveys.

There’s also a pointer to some medical advice, which is where the whole thing gets a bit more dodgy. The only reason I’m keeping this to “a bit” is that I don’t think you’re intended to really take the story seriously:

“Masturbation can produce the right environment for a strengthened immune system,” she told Men’s Health. 

Her views are backed up by a study from the Department of Medical Psychology at the University Clinic of Essen which looked at the effects of orgasm through masturbation on the white blood cell count.

A group of 11 volunteers were asked to participate in a study and the results confirmed that sexual arousal and orgasm increased the number of white blood cells.

The study is actually linked. It’s a paywalled paper, but here’s the abstract.

If you’ve got an experimental study of an intervention that might prevent viral infection, you’d want to know who was being studied, the sample size, and how representative they were.  You’d want to know what effects were being measured and over what period.  And you’d want to know to what extent the intervention was also present in the control group. In a serious clinical trial that sort of information would be in the abstract.

The abstract doesn’t actually say anything about the diversity of study population, apart from “11 volunteers”. The paper says “healthy young males” and notes they were all exclusively heterosexual and had an average age of 37.7 (so ‘young’ is being interpreted relatively broadly).  The participants were asked to refrain from sexual activity for 24 hours before the experiment, but that’s all.

The abstract does talk, importantly, about “transient” changes in hormones. It’s less open about the changes in white blood cells.  The headline effect is that there were more “NK cells“, which are theoretically relevant to viral infection, 5 minutes after orgasm.  It’s not clear whether the increase is big enough to be helpful. However, the increase had gone away again by the second measurement at 45 minutes (so it’s probably safe). Here’s the graph

It’s not clear that we should believe these results, given the well-known problems with reporting and analysis bias in small experiment — and even without any issues in the scientific publication process, you can be pretty confident Newshub wouldn’t have mentioned unconfirmed results from a tiny experiment published in 2004 if it didn’t confirm what they wanted to say.  But suppose we do believe the results.  What does it tell us about COVID-19? Is this, as they say, news you can use? You might consider your times of greatest exposure to other people’s viruses and look for a half-hour window where greater immunity would be relevant. On the other hand, that might cause more problems than it solves. Alternatively, you could just wash your hands (actually, you should wash them either way).

Leaving aside the questions of appropriate time and place, I think the StatsChat advice on red wine and chocolate also applies here. If you’re thinking of a half-hour increase in one type of white blood cells as a convincing argument in favour of orgasms, you may be doing them wrong.

There are lots of questions about the current pandemic that need expertise in microbiology or international freight logistics or sociology or whatever, but there’s the occasional one that is basically statistical.  In particular,  lots of people would like to know how bad COVID-19 actually is: what’s your (or your kid, or your grandmother’s)  chance of needing hospital treatment or dying?  This post will try to explain why we don’t know the answer, and aren’t going to know the answer for a while, although there are some questions that sound similar where we do know the answer or will know fairly soon.

The mortality rate (case fatality rate) for a disease is the number of people who die from it divided by the number of people who catch it.  For the initial outbreak in China we have a reasonably good idea of the number of people who died (at least if you trust the PRC statistics), and the rest have recovered. We don’t know how many people were infected; the health system had more urgent things to do than testing apparently healthy people. The same is likely true for some of the smaller outbreaks in other Asian countries.  In the rest of the world we don’t even know the numerator of the rate, because most of the people who have been sick are still sick and we have to wait to see how many recover and how many die.

To some extent the mathematical epidemic models can work around this problem.  If people with few or no symptoms are still infectious,  they’ll contribute to the growth of the epidemic, and the number can be estimated from the shape of the epidemic curve.  That doesn’t work perfectly, but it works to some extent.  However, if people with few or no symptoms are less infectious, they’ll tend to be missed. People who have no symptoms and who don’t pass the virus on are invisible to the models, at least until there are enough people like that to get herd immunity working.  This post on Andrew Gelman’s blog looks at two fairly sophisticated modelling attempts, which don’t agree all that closely.

In the long run, it will be possible to get a reliable estimate of the number of people who have been infected, because they will end up with antibodies to the virus, and someone will develop a test for the antibodies and apply it to a suitable population sample.  That sort of data goes into the mortality rate estimates for flu: the mortality rate among people who develop classic, serious, flu symptoms is quite high, but there are a lot of people who are infected without ever knowing it — as much as 10% of the population — so the mortality rate among everyone infected is very low. In the same way, the retrospective mortality rate of COVID-19 will likely be lower (by some unknown factor) than the current ratio.

We do have reasonably good information on what happens to people who get sick enough to need medical attention, and  we know how that number grows with good or not so good control efforts. That’s the number that matters if you get sick. But we don’t know as much as we’d like about the structure of the epidemic and how many people will eventually get seriously ill, because we haven’t been able to find and count the subset of basically healthy cases.

Team Ratings for Round 7

The basic method is described on my Department home page.
Here are the team ratings prior to this week’s games, along with the ratings at the start of the season.

Performance So Far

So far there have been 40 matches played, 25 of which were correctly predicted, a success rate of 62.5%.
Here are the predictions for last week’s games.

Predictions for Round 7

Here are the predictions for Round 7. The prediction is my estimated expected points difference with a positive margin being a win to the home team, and a negative margin a win to the away team.

Team Ratings for Round 14

The basic method is described on my Department home page.
Here are the team ratings prior to this week’s games, along with the ratings at the start of the season.

Performance So Far

So far there have been 78 matches played, 52 of which were correctly predicted, a success rate of 66.7%.
Here are the predictions for last week’s games.

Predictions for Round 14

Here are the predictions for Round 14. The prediction is my estimated expected points difference with a positive margin being a win to the home team, and a negative margin a win to the away team.