On July 30, Israel began administering third doses of mRNA vaccines to targeted groups of people. This decision was controversial since there is no science to support it. The policymakers do have educated guesses by experts based on best-available information. By science, I mean actual evidence. Since no one has previously been given three shots, there can be no data on which anyone can root such a decision. Nevertheless, the pandemic does not always give us time to collect relevant data, and so speculative analysis has found its calling.

Dvir Aran, at Technion, has been diligently tracking the situation in Israel on his Twitter. Ten days after July 30, he posted the following chart, which immediately led many commentators to bounce out of their seats crowning the third shot as a magic bullet. Notably, Dvir himself did not endorse such a claim. (See here to learn how other hasty conclusions by experts have fared.)

When you look at Dvir's chart, what do we see?

Dvir_aran_chart

Possibly one of the following two things, depending on what concern you have in your head.

1) The red line sits far above the other two lines, showing that unvaccinated people are much more likely to get infected.

2) The blue line diverges from the green line almost immediately after the 3rd shots started getting into arms, showing that the 3rd shot is super effective.

If you take another moment to look, you might start asking questions, as many in Twitter world did. Dvir was startlingly efficient at answering these queries.

A) Does the green line represent people with 2 or 3 doses, or is it strictly 2 doses? Aron asked this question and got the answer (the former):

AronBrand_israelcases_twoorthreedoses

It's time to check our presumptions. When you read that chart, did you presume it's exactly 2 doses or did you presume it's 2 or 3 doses? Or did you immediately spot the ambiguity? As I said in this article, graphs attain efficiency at communication because the designer leverages unspoken rules - the chart conveys certain information without explicitly placing it on the chart. But this can backfire. In this case, I presumed the three lines to display three non-overlapping groups of people, and thus the green line indicates those with 2 doses but not 3. That presumption led me to misinterpret what's on the chart.

B) What is the denominator of the case rates? Is it literal - by that I mean, all unvaccinated people for the red line, and all people with 3 doses for the blue line? Or is the denominator the population of Israel, the same number for all three lines? Lukas asked this question, and got the answer (the former).

Lukas_denominator

C) Since third shots are recommended for 60 year olds and over who were vaccinated at least 5 months ago, and most unvaccinated Israelis are below 60, this answer opens the possibility that the lines compare apples and oranges. Joe. S. asked about this, and received an answer (all lines display only 60 year olds and over.)

Joescholar_basepopulationquestion

Jason P. asked, and learned that the 5-month-out criterion is immaterial since 90% of the vaccinated have already reached that time point.

JasonPogue_5monthsout

D) We have even more presumptions. Like me, did you presume that the red line represents the "unvaccinated," meaning people who have not had any vaccine shots? If so, we may both be wrong about this. It has become the norm by vaccine researchers to lump "partially vaccinated" people with "unvaccinated", and call this combined group "unvaccinated". Here is an excerpt from a recent report from Public Health Ontario (link to PDF), which clearly states this unintuitive counting rule:

Ontario_case_definition

Notice that in this definition, someone who got infected within 14 days of the first shot is classified as an "unvaccinated" case and not a "partially vaccinated case".

In the following tweet, Dvir gave a hint of what he plotted:

Dvir_group_definition

In a previous analysis, he averaged the rates of people with 0 doses and 1 dose, which is equivalent to combining them and calling them unvaccinated. It's unclear to me what he did to the 1-dose subgroup in our featured chart - did it just vanish from the chart? (How people and cases are classified into these groups is a major factor in all vaccine effectiveness calculations - a topic I covered here. Unfortunately, most published reports do a poor job explaining what the analysts did).

E) Did you presume that all three lines are equally important? That's far from true. Since Israel is the world champion in vaccination, the bulk of the 60+ population form the green line. I asked Dvir and he responded that only 7.5%, or roughly 100K are unvaccinated.

DvirAran_proportionofunvaccinated

That means 1.2 million people are part of the green line, 12 times higher. There are roughly 50 cases per day among unvaccinated, and 370 daily cases among those with 2 or 3 doses. In other words, vaccinated people account for almost 90% of all cases.

Yes, this is inevitable when over 90% of the age group have been vaccinated (but it is predictable on the first day someone blasted everywhere that real-world VE is proved by the fact that almost all new cases were in the unvaccinated.)

If your job is to minimize infections, you should be spending most of your time thinking about the 370 cases among vaccinated than the 50 cases among unvaccinated. If you halve the case rate, that would be a difference of 185 cases vs 25. In Israel, the vaccination campaign has already succeeded; it's time to look forward, which is exactly why they are re-focusing on the already vaccinated.

***

If what you worry about most is the effectiveness of the original two-dose regimen, Dvir's chart raises a puzzle. Ignore the blue line, and remember that the green line already includes everybody represented by the blue line.

In the following chart, I removed the blue line, and added reference lines in dashed purple that correspond to 25%, 50% and 75% vaccine effectiveness. The data plotted on this chart are unadjusted case rates. A 75% effective vaccine cuts case rate by three quarters.

Junkcharts_dviraran_israel_threeshotschart

This chart shows the 2-dose mRNA vaccine was nowhere near 90% effective. (As regular readers know, I don't endorse this simplistic calculation and have outlined the problems here, but this style of calculation keeps getting published and passed around. Those who use it to claim real-world studies confirm prior clinical trial outcomes can either (a) insist on using it and retract their earlier conclusions, or (b) admit that such a calculation was, and is, a bad take.)

Also observe how the vaccinated (green) line is moving away from the unvaccinated (red) line. The vaccine apparently is becoming more effective, which runs counter to the trend used by the Israeli government to justify third doses. This improvement also precedes the start of the third-shot campaign. When the analytical method is bad, it generates all sorts of spurious findings.

***

As Dvir said, it is premature to comment on the third doses based on 10 days of data. For one thing, the vaccine developers insist that their vaccines must be given 14 days to work. In a typical calculation, all of the cases in the blue line fall outside the case-counting window. The effective number of cases that would be attributed to the 3-dose group right now is zero, and the vaccine effectiveness using the standard methodology is 100%, even better than shown in the chart.

There is an alternative interpretation of this graph. Statisticians call this the selection effect. On July 30, the blue line split out of the green: some people were selected to receive the 3rd dose - this includes an official selection (the government makes certain subgroups eligible) as well as a self-selection (within the eligible subgroup, certain people decide to get the 3rd shot earlier.) If those who are less exposed to the virus, or more risk averse, get the shots first, then all that is happening may be that we have split off a high VE subgroup from the green line. Even if the third shot were useless, the selection effect itself could explain the gap.

Statistics is about grays. It's not either-or. It's usually some of each. If you feel like Groundhog Day, you're getting the picture. When they rolled out two doses, we lived through an optimistic period in which most experts rejoiced about 90-100% real-world effectiveness, and then as more people get vaccinated, the effect washed away. The selection effect gradually disappears when vaccination becomes widespread. Are we starting a new cycle of hope and despair? We'll find out soon enough.

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