8 ms·

That’s not all that huge when there’s such a small number of deaths in the given group over that time. This is part of the reason a lot of drugs later prove to

That’s not all that huge when there’s such a small number of deaths in the given group over that time. This is part of the reason a lot of drugs later prove to be useless… I also don’t see a citation for the 13% reduction in all cause mortality. To be honest, that’s an insanely weird metric to review for a malaria vaccine. Why not malaria related deaths? Total in 2015 study [1]: > 8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Total deaths: …? Are we talking 8 deaths in the control group and 7 in those injected? This isn’t clear at all to me [1] https://pubmed.ncbi.nlm.nih.gov/25913272/ https://pubmed.ncbi.nlm.nih.gov/25913272/ On page 20 of the 2021 report we see 1443 deaths in comparison group and 1421 in implementing group [2]. With a pretty wide margin of error I might add. Is that what they’re reporting…? [2] https://www.nitag-resource.org/sites/default/files/2022-05/Milligan-Moore-2021-statistical-report-rtss-pilot-evaluation.pdf https://www.nitag-resource.org/sites/default/files/2022-05/M...

michaelrpeskin 3y ago
Actually, all cause is the right metric. Let's say the vaccine stops 100% of malaria but causes severe heart attacks. You'd probably want to know that. I didn't review _this_ study, so I won't comment on the quality of analysis, but what you want to know about a vaccine is "effectivity" does it stop contraction and spread of the illness and "safety" does it not cause any other problems that in aggregate are worse than the illness (all cause mortality is one metric here).
- Fomite 3y ago
  And indeed there are a number of trials that show a decrease in all cause mortality (mass childhood administration of azithromycin comes to mind) that we'd miss if we were just looking at already known endpoints.
roywiggins 3y ago
All-cause mortality is easier to measure, it also takes into account any deaths caused by the vaccine, and any deaths caused by non-malaria proximate causes that would nevertheless have been averted by the vaccine. Malaria is really bad for you even if you survive it, and probably makes you more vulnerable to dying of other things: "For instance, clinical malaria is known to exhaust T cells, he says, and vaccination, by preventing infection, might therefore leave T cells readier to combat other pathogens. Such a general survival benefit has been documented for measles and tuberculosis vaccination. Other leading causes of death in the young children in these areas include pneumonia and diarrhea caused by pathogens including Streptococcus pneumoniae and rotavirus." So, surviving malaria could very easily make it harder to survive your next encounter with rotavirus; vaccinating against malaria would then reduce deaths from rotavirus.
- timr 3y ago
  Yeah, but...it's also subject to sample bias. Especially in a place like east Africa, having enough resources (not just money -- time, transport, etc.) to get a crazy expensive new vaccine could easily have co-variates that affect all-cause mortality. It's great to report it, but you definitely want to see the cause-specific numbers, too.
  - deleted 3y ago
    [deleted]
  - roywiggins 3y ago
    They used two sets of controls: 1, an entire set of communities where the vaccination wasn't offered at all, and 2, children who were not eligible due to age. They weren't just comparing children who got the vaccine with children who didn't, they were comparing children who were eligible for the vaccine and those who weren't, and that couldn't have been so easily confounded: "79 areas where the RTS,S vaccine was administered and 79 comparator areas where it was not available" "Researchers then compared the death rates of babies whose age made them eligible to receive three doses of the vaccine with those of young children who were not age-eligible for three doses, in both RTS,S areas and unvaccinated areas." This is obviously not foolproof, but it seems like a substantial bulwark against obvious confounders. If you can show that 1) the mortality rate in the vaccinated communities was lower in the age-eligible children than not-age-eligible[0] and 2) this effect was absent in unvaccinated communities that seems like it goes quite far towards proving that it's real and not an artifact. It probably even underestimates how protective it is at an individual level. (communities which had the vaccine offered also had fewer cases of severe malaria recorded in their hospitals, so there's a straightforward reason to think it does something) [1] okay probably age-ineligible children have a different mortality rate regardless. You'd be taking the difference between those two groups of children and comparing it to the same difference in communities without the vaccination offered. This difference-of-difference would tell you whether the vaccine is doing anything. It wouldn't matter if only the richer children received the vaccine if the communities have basically the same distribution of wealth since you're comparing differences between age cohorts, not between vaccinated and unvaccinated.

michaelrpeskin 3y ago

Actually, all cause is the right metric. Let's say the vaccine stops 100% of malaria but causes severe heart attacks. You'd probably want to know that. I didn't review _this_ study, so I won't comment on the quality of analysis, but what you want to know about a vaccine is "effectivity" does it stop contraction and spread of the illness and "safety" does it not cause any other problems that in aggregate are worse than the illness (all cause mortality is one metric here).

Fomite 3y ago
And indeed there are a number of trials that show a decrease in all cause mortality (mass childhood administration of azithromycin comes to mind) that we'd miss if we were just looking at already known endpoints.

roywiggins 3y ago

All-cause mortality is easier to measure, it also takes into account any deaths caused by the vaccine, and any deaths caused by non-malaria proximate causes that would nevertheless have been averted by the vaccine. Malaria is really bad for you even if you survive it, and probably makes you more vulnerable to dying of other things: "For instance, clinical malaria is known to exhaust T cells, he says, and vaccination, by preventing infection, might therefore leave T cells readier to combat other pathogens. Such a general survival benefit has been documented for measles and tuberculosis vaccination. Other leading causes of death in the young children in these areas include pneumonia and diarrhea caused by pathogens including Streptococcus pneumoniae and rotavirus." So, surviving malaria could very easily make it harder to survive your next encounter with rotavirus; vaccinating against malaria would then reduce deaths from rotavirus.

timr 3y ago
Yeah, but...it's also subject to sample bias. Especially in a place like east Africa, having enough resources (not just money -- time, transport, etc.) to get a crazy expensive new vaccine could easily have co-variates that affect all-cause mortality. It's great to report it, but you definitely want to see the cause-specific numbers, too.
- deleted 3y ago
  [deleted]
- roywiggins 3y ago
  They used two sets of controls: 1, an entire set of communities where the vaccination wasn't offered at all, and 2, children who were not eligible due to age. They weren't just comparing children who got the vaccine with children who didn't, they were comparing children who were eligible for the vaccine and those who weren't, and that couldn't have been so easily confounded: "79 areas where the RTS,S vaccine was administered and 79 comparator areas where it was not available" "Researchers then compared the death rates of babies whose age made them eligible to receive three doses of the vaccine with those of young children who were not age-eligible for three doses, in both RTS,S areas and unvaccinated areas." This is obviously not foolproof, but it seems like a substantial bulwark against obvious confounders. If you can show that 1) the mortality rate in the vaccinated communities was lower in the age-eligible children than not-age-eligible[0] and 2) this effect was absent in unvaccinated communities that seems like it goes quite far towards proving that it's real and not an artifact. It probably even underestimates how protective it is at an individual level. (communities which had the vaccine offered also had fewer cases of severe malaria recorded in their hospitals, so there's a straightforward reason to think it does something) [1] okay probably age-ineligible children have a different mortality rate regardless. You'd be taking the difference between those two groups of children and comparing it to the same difference in communities without the vaccination offered. This difference-of-difference would tell you whether the vaccine is doing anything. It wouldn't matter if only the richer children received the vaccine if the communities have basically the same distribution of wealth since you're comparing differences between age cohorts, not between vaccinated and unvaccinated.