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What is the landscape of uncertainty outside the clinical trial’s methods?

I live in the province of British Columbia in the country of Canada (right, this post is not by Andrew, it is by Lizzie). Recently one of our top provincial health officials, Dr. Bonnie Henry, has received extra scrutiny based on her decision to delay second doses of the vaccine. The general argument against this is the one I have heard from Dr. Fauci of the US, who has been various levels of adamant that you do what the trial did (I would say very adamant, very adamant, very adamant, then slightly less adamant after the kerfuffle with the UK). You don’t deviate from the methods of the trial.

This has got me wondering what the landscape of uncertainty looks like as you move away from the methods of a clinical trial. And what progress we’ve made — if any — on this in the last couple of decades, when I first realized how stark the divide between inside and outside the trial methods is for many.

Over 15 years ago I was helping take care of a 50-year-old family member who had cancer and was struggling to get through a 6 week regime of radiation + chemotherapy at a major cancer institute in Boston. She had gotten through the first couple of weeks okay, even driving herself the 6-8+ round-trip hours from her home to the institute five days a week for her daily radiation appointments. But things got progressively worse in the third and following weeks (when I was her trusty chauffeur and companion). By her fifth week she was in and out of the ER with various major issues and was receiving various infusions to attempt to prop up her system so she could survive the next dose of radiation. Every day before radiation she needed a series of tests followed by a visit to her oncologist to get approval for that day’s dose of radiation, and this did not seem out of the ordinary for the later weeks of high-dose radiation therapy.

At one visit, when things were going particularly poorly, the radiation oncologist was brought in to consult on whether to continue treatment. He was advising for continuing, though it would be hard. It took a lot of her energy to speak, so she was often quiet, but on this day she asked him: ‘why do I have to do this? I have done this for most of the 30 visits, why do these last few matter so much?’ And he told her the truth — “because we only have data on the people who get the full dose. We don’t know what happens if you don’t take the full dose, or you take a few days off before continuing.” It was very helpful. I remember she said something along the lines of ‘okay,’ and we drove home in semi-shock, but at least we knew why they were pushing for this now. It was always her choice, but until then neither of us realized how gaping the uncertainty was between, say, going for 27 of your total 30 radiation visits, and going for all 30.

Clearly, the ethics matter, and that’s especially clear with a highly infectious and deadly disease like Covid. I assume that many of these deviant public health officials who have delayed second doses have done the simple SIR model math and figured out that: (n higher number of people vaccinated at X% efficacy given Y weeks of delaying the second dose)*(black box uncertainty as you deviate away from the trial methods)=likely more lives saved. Henry has cited studies showing >90% efficacy for the three weeks after the first dose of the Moderna and Pfizer vaccines, so I suspect she’s feeling good that her X in extending the second dose to four months is still fairly high and thus has some internal estimate on the landscape of uncertainty beyond the methods of the trial, and there’s growing data on this.

But if you listen to various interviews with Fauci and other public health officials, I start drifting into memories of discussions that start with, ‘what is the variance of a fixed effect? It’s either 0 or infinity.’ Now, I don’t mean exactly that — but I do mean there seems to be a large gap in perspectives here. In one — the clinical trial methods must be followed to a T, until a new or properly vetted trial of any deviation is approved, conducted and reviewed. And in another — some adjustments happen given the potential for lives saved despite the uncertainty and that ‘population health data’ is then used to make further adjustments on the fly (in conjunction with other ways of viewing the clinical trial data you have).

These debates have made me wonder what progress have we made addressing this uncertainty from both a bioethics, and data collection and design standpoint? I am not (at all) a bioethicist but the rigid adherence to the trial methods doesn’t feel terribly ethical to me, and I think Covid has highlighted that. So I wonder how much has changed in last 10, 20 or 30 years of how those who deviate or ‘drop out’ of clinical trials are handled as datapoints. Are they required to be tracked? Or is it better to save money by focusing only on those who follow the trial perfectly? Is there an incentive for research or new methods or databases that compile these deviants to start fleshing out that landscape of uncertainty beyond the clinical trial methods? Or is everything beyond basically zero, or maybe infinity? Or maybe somewhere in between.

194 Comments

  1. Christian Hennig says:

    I’d think that there’s not only the trial but also some medical/biochemical knowledge behind the decision to run the trial like this. Surely when making decisions about deviation from what was investigated by the trial this knowledge must be brought in somehow, and may or may not suggest how bad or not so bad an idea it could be to deviate?

  2. Joshua says:

    Lizzie –

    >… but the rigid adherence to the trial methods doesn’t feel terribly ethical to me,

    You have an estimate that the vaccine has an efficacy within a particular range.

    You can project those probabilities one way or the other but if you alter the protocol you run the risk of 0% efficacy, or even worse, is there some likelihood of creating a phenomenon of resistence by allowing a virus to linger and regroup?

    That seems to me to be a huge burden for policy-makers. This is very difficult decision-making about potentially very high damage (if low probability) risk. At some level values come into play. But I don’t understand why you put this within a framework of ethics.

    • Eric says:

      I definitely see this as an ethical question (like much of public health and healthcare). In the absence of complete data, decisions still need to be made (but based on the data that is available.) And when priors, data, and models don’t give a feasible decision (which would be to vaccinate EVERYONE with two doses), ethics is the name of the game.

    • Michael J says:

      There’s definitely a tail risk with deviating from the protocol but I think there’s also a tail risk with staying with the protocol. If you believe delaying the second dose is more effective then that means sticking with the current scheme means the pandemic will be unnecessarily longer which means more time for troublesome variant shenanigans to arise. As a layperson it’s hard to say which is more of a worrisome tail risk (and I don’t know if even experts would know this, there’s just so much uncertainty) but it seems like ending the pandemic as soon as possible should be the primary priority.

      Also, I think an ethical framework might be beneficial here because well thought out heuristics may outperform formal models when there’s a lot of uncertainty. Though to be honest I don’t know much about bioethics and what they have to contribute to this issue.

      • Joshua says:

        Michael –

        > There’s definitely a tail risk with deviating from the protocol but I think there’s also a tail risk with staying with the protocol.

        I agree. I wasn’t dismissing that possibility. In fact, part of my thinking is that tails wag in lots of different directions and I don’t see how choosing a direction here boils down to an ethical choice.

        Particularly if you know with a reasonable degree of certainty that the existing protocol brings benefit. It might make sense to risk that benefit for the potential of a greater benefit, and one shouldn’t just ignore that potential, but I just can’t see how one determines which choice is ethically superior unless the balance of uncertainties is relatively unambiguous. I don’t think that’s the case here although I could be convinced otherwise.

        • Michael J says:

          Ethics can come in a few different ways. I don’t know much about it so maybe I’m off the mark but this is how I’m thinking about it:

          There are ethical concerns within a utilitarian / cost-benefit approach where you model, say deaths, under the two regimes and calculate point estimates and uncertainty intervals and then compare the two. The ethics decision here might be how to weigh expectation maximization against variance minimization. I think this is how you may be thinking about ethics? And in this scenario ethics would not be relevant if we can’t create models to begin with (more on this point at the end).

          Alternatively, I think one can use ethics to reject the entire idea of minimizing deaths or whatever outcome. Like Michael Nelson mentions below about “do no harm”. Under that framework, the existing policy is the default and given a lot of weight. So even if the two regimes have the same point estimates and uncertainty intervals you would strongly favor the existing policy. At least that’s how I see it but I think proponents of that way of thinking may disagree (but I do acknowledge that it’s a bit more complicated than how I said it). In general, I don’t really like these alternative frameworks but maybe some are useful.

          Back to this specific situation: there’s a recent preprint (hat tip Marginal Revolution) that seems to argue that there’s more risk regarding mutations on the do not delay second dose side than there is on the delay second dose side. I haven’t read it yet though, just the abstract and the excerpts posted on MR.

          https://dash.harvard.edu/bitstream/handle/1/37366988/Dose_sparing_evolution.pdf

      • Michael Nelson says:

        I’ve always liked the ethical framework of “First, do no harm.” It’s nice, because, it says what the primary priority should be right in the framework!

        Seriously, though, from that perspective, we should not be weighing “on-protocol deaths” against “off-protocol deaths,” we should be weighing “allowing deaths” versus “causing deaths.” Sticking with the protocol, until we have evidence that doing otherwise is safe and effective, may result in more deaths–we don’t know–but we won’t have caused them.

        • Joshua says:

          Michael –

          > I’ve always liked the ethical framework of “First, do no harm.” It’s nice, because, it says what the primary priority should be right in the framework!

          I don’t understand in this context where the “doing harm” is. Is it delaying the 2nd dose or not delaying the 2nd dose? Which is the ethical decision?

    • Lizzie says:

      > if you alter the protocol you run the risk of 0% efficacy, or even worse, is there some likelihood of creating a phenomenon of resistence by allowing a virus to linger and regroup?

      I think this is the framing I hear often, and it seems a little extreme. Sure, we run the risk of 0% efficacy, but we have a lot of information that says we are unlikely approaching 0% efficacy with these delayed doses, so why act as though this is an important possibility we need to avoid and instead build on data and modeling?

      I think there *is* a real fear that if we don’t vaccinate enough we’ll miss the likely now small chance to eradicate the virus (https://www.nature.com/articles/d41586-021-00396-2) and it will evolve. But we’re not exactly coming up with the dosing strategy to avoid virus evolution — if that were our goal we would be taking a much more global approach to vaccination because the goal with vaccination is fewer deaths and herd immunity (only the latter mattering to slowing virus evolution) … and getting to herd immunity faster is part of the argument to delay second doses.

      • Brent Hutto says:

        If anyone has been operating with the goal of eradicating COVID-19, well I hope they weren’t in a position to seriously gum up the works. That is not a remotely plausible outcome and thinking there is even a “small chance” of doing so should not guide public policy.

        The vast majority of people who wish to receive a COVID-19 vaccine (at least in the developed world) will eventually have a chance to do so. If there’s only one specific dosage and timing that was subjected to a clinical trial it seems obvious that you administer in that manner and not trying to vaccinate more people, sooner, while hoping this ad hoc, untested method also works to some extent.

  3. Thanatos Savehn says:

    This reminds me of the 2018 discovery that low dose dexamethasone for myeloma produces much better outcomes than the high doses used for many years. Dex’s severe side effects (e.g. rhabdomyolysis) were first recognized 50+ Years ago but the doctors kept giving the high dose despite severe side effects in myeloma patients. Why? It’s the dose used in the lenolidomide trial that showed improved survival. Why not try a lower dowe? It’s the only dose for which they had data.When a trial of low dose dex was finally run side effects were greatly reduced and survival increased by 1/8. It makes you wonder how much pain and death could be avoided if the uncertainties that come with a trial were more widely recognized.

    • Martha (Smith) says:

      Thank you for this example. It does point out well that we should not automatically stop studying a treatment when one clinical trial has been finished.

      And (having had a sibling die of cancer a few weeks ago), I wonder if it might be worthwhile to try some clinical trials that involve things like giving the patient the option of transferring to hospice care at any time during the clinical trial. That could give useful information on patients’ perspectives on willingness to endure severe side effects of treatments being studied.

  4. Andrew says:

    Lizzie:

    You raise a good question, and I don’t think enough has been written about the steps from (a) inference about a particular experimental condition to (b) decisions of what to do in the wild. One useful framing could be in terms of treatment interactions. We don’t typically have enough data to estimate interactions of interest, but these interactions are crucial in deciding what flavor of treatment to use.

    • Michael Nelson says:

      Don’t know if you’ve followed this, Andrew, but the EU is taking interactions very seriously right now, and doing a terrible job of it. That is, they are chasing rumors and small studies that suggest the AstraZeneca vaccine doesn’t work for seniors, particularly in France and Germany.

    • Lizzie says:

      Yes, I assume the scaling hurdle of interactions is much of the issue. But there’s also what happens to data once protocols become the ‘standard of care.’ If data are centralized maybe eventually there are enough consistent deviants for useful inference (but maybe there is no incentive to do those analyses)? Or maybe there is still a strong push to get so many to follow the protocol that you end up with mostly data repeating the trial methods and then you can continue to improve your effect size estimate and that’s the aim? Or maybe there is bias in where the deviations from protocol happen … or we just don’t centralize data.

      And I do find how this uncertainty is communicated to the public and patients less than ideal, but that’s from my very personal perspective.

      • sam says:

        Hey Lizzie and Andrew,

        I can see how interactions can be part of the problem but seems like you’re now entering into observational causal inference territory.

        Seems like the hypothetical you described could be answered if we allow the ‘treatment’ to be a multivariate vector (could include number of times given treatment, time between treatments, dose amount, etc).

        However, in the problem you described then the ‘treatment’ would not be randomly assigned but (at least in part) be self assigned.

        At which point you can use some observational causal methods (propensity scores, matching, etc) to get back at the causal effect of these treatments. But that would sort of mitigate the benefits of doing a random trial in the first place.

        It appears that you can get the benefits of a random treatment assignment is contrary to having people choose they’re treatment.

  5. Dale Lehman says:

    Strict adherence to the trial guidelines can be motivated by a number of less-than-ideal factors (as is constantly pointed out by Alex Tabarrok on Marginal Revolution). For example, it is safer for your reputation since you can always blame the guideline. In the case of one dose vs. two, it also is relatively easy for risk averse public health officials. Tabarrok makes a strong case that one dose to as many people as possible, before second doses, is the rational policy choice. I am not convinced, but there are plenty of arguments both ways.

    So, the general question you raise should certainly depend on the quality of the evidence we have for deviating from the trial guidelines. And we have some, but not nearly enough, and not clear enough to conclude anything. The biggest problem I have with deviating from the guidelines is that it opens the door to almost anything. In our world of false facts, this seems enormously dangerous to me. But it also seems unwise to be too rigid, and it seems unethical to do so regardless of the individual case (such as the one you describe). I doubt there can be any clear rules applied to such circumstances. The trial guidelines are based on some evidence. As additional evidence is gathered, there may be reasons to consider deviating from those guidelines. But the standards for evidence and analysis seem no different than for anything, including the original trial protocol. There is bad analysis and better analysis (and worse analysis). If we ignore any legal ramifications and vested interests, we are left with the same uncertainty we face in virtually every public and personal decision.

    A bit off the main topic, but along the same lines, there is the issue of “intention to treat.” Virtually all medical studies (as far as I know) use intention to treat to group trial participants – some of whom end up refusing the random treatment they were assigned to. If we use the actual treatment received, the results can differ (I’ve seen some studies that show a big difference). I’ve never found intention to treat very sensible – the actual treatment would seem to me to be a better measure of an intervention’s effectiveness. However, it does raise selection issues.

    • Michael Nelson says:

      Dale, your second point is interesting. It is now somewhat standard in education research for new interventions to be tested in two phases. The first is an “efficacy” trial, where fidelity may be artificially boosted, and/or the analyses may focus on the “treatment on treated,” in order to show that the intervention works under ideal circumstances. The second is an “effectiveness” or “scale-up” trial that measures the effects in a realistic setting. I believe the main motivation for this model has something to do with the practical and political fights in federal funding of education research in the early 2000’s, when there was a sudden shift from funding lots of development and demonstration projects, to awarding huge grants for very rigorous, large-scale RCTs of the few interventions that had strong correlational or limited experimental evidence already. There appears to have been a compromise, where education researchers have become more quantitative and the agencies fund more opportunities to develop rigorous evidence. Anyway, it’s a different model.

    • Daniel H. says:

      I agree on the “incentives matter” framing. If we push officials to be as risk-averse as possible, thats what we get. Are there counterexamples, eg countries doing much better?

  6. Michael Nelson says:

    There’s a vast difference between individualizing treatment and revising official treatment protocols. In the public health context, that probably wouldn’t mean literally designing a different treatment protocol for each person, but I’d at least like to see some debate about, maybe, spacing out doses over a period of time based on the risk level of a person or the caseload in a region. But the whole idea of tinkering based on supply-and-demand becomes a lot less palatable if, instead of calling it “delaying second doses,” we call it “denying patients the approved treatment and substituting an unapproved one.” Especially given (my perception that) the biggest obstacle so far has been efficient distribution, not supply.

    • Martha (Smith) says:

      Michael said,
      “Especially given (my perception that) the biggest obstacle so far has been efficient distribution, not supply.”

      I see “efficient distribution” and “supply” as overlapping problems: Inefficient distribution at the top level often creates inadequate supply at lower levels.

      • Michael Nelson says:

        Not so much overlapping as causal. Fix the distribution, the supply improves. Increase the supply, overwhelm an already precarious distribution system. “The spice must flow!” (Please excuse my irrepressible nerd instincts.)

        • Michael J says:

          For the specific situation of delaying second doses I’m not sure that tradeoff is true, if I’m understanding you correctly. Like it doesn’t matter administratively, I think, whether a clinic makes two appointments for two people or two appointments for one person. The burden on the system should be the same under both scenarios but in the first you get two people vaccinated versus just one in the latter.

  7. Phil says:

    1. If the radiation trial was only done for 30 days with nobody missing a day, there’s pretty much no chance that is optimal on average, think of how spectacularly lucky that would be.
    2. Even if it were somehow optimal on average, it would still be spectacularly unlikely that it would be optimal for this particular woman.
    3. If the radiation and its side effects weren’t going to kill her, then presumably it’s better to do more days because you kill more cancer cells. And skipping a day could let some cells recover that would otherwise be killed. On the other hand, if skipping a few days let her recover strength so that she could survive another week of radiation (say), this she could potentially come out ahead.
    4. The people who ran the trial presumably do not think there’s an enormous difference between 28, 30 and 32 days for example: if they thought 32 had a decent chance to be much better than 30 then they would have run a trial at 32.

    Putting it all together: I think there’s good reason to tell people to do as many days as they can tolerate (or survive!), up to around 30. 30 days of radiation should be better than 27, when it comes to extending life, all else equal. But all else is not equal, and once someone is having to go to the ER and have various life-saving treatments just to survive the radiation, there has to be at least a decent chance you’re doing more harm than good.

    • Lizzie says:

      I generally agree. On your point 4, I do wonder how often longer treatment regimes run in 5 day intervals (aka, the length of a midweek) and that we lack inference especially the further away you get from n/5. Especially as radiation is mostly about the total dose I can see the rationale to focus studies on varying that instead of length or other treatment decisions.

  8. CvC says:

    I am not sure I see an ethics (whatever that means) problem, it is on the contrary a very down-to-earth and material question.

    It is intellectual laziness of the highest order (and borderline religious) to keep repeating you must do exactly as the trials did. It may also be out of a desire to not take responsibility for anything.

    This is the same issue with Oxford-AstraZeneca for older people: the effect was not tested so it does not exist. We are supposed to believe that, somehow, after 65 years of age, the mechanisms of this vaccine that work for younger people and the mechanisms of other vaccines that work for all ages stop existing.

    But nobody ever wondered if the vaccine work for a 35-year-old redhead woman with an engineering degree having emigrated from Canada to Florida before the age of 12, even though I bet there was none on the trial.

    • confused says:

      I wonder if part of the issue is that the FDA etc. are fairly old organizations, and biological knowledge has advanced *massively* in recent decades. Could this be a factor — IE the way the organization makes decisions implicitly includes the assumption that prior/general biological knowledge is not very useful (because it wasn’t in the 1930s, or even 1962)?

      I do think the avoidance of responsibility for risky decisions (as in any bureaucracy) is at least as important, though?

  9. BrianM says:

    Being UK based, this is something that has given me some concern since the UK introduced the delay for the second COVID vaccine does. I know my personal preference would be, for example, my elderly mother to get her second dose on the schedule rather than me (who is outside vulnerable groups) get my first one earlier. That this is, inevitably, being trialled on some of the most vulnerable to my mind makes it indefensible.

    However, this is based on a basic presumption. I would have thought that at phase 1 or phase 2, tests were done to determine the best interval between vaccines. I’d imagine these would be low powered due to the small numbers, but I haven’t seen anything data that this was done or what the variability was. If these showed little difference between 4 & 12 weeks I might be somewhat reassured. I do know there is some monitoring going on – a couple of friends who work at a hospital are on the 12 week interval, but do twice weekly swab tests. It does seems a bit late thought. Anyway, anyone seen any data on trials of different intervals, or even know if its been done?

  10. Jon Baron says:

    How hard would it be to modify clinical trials (e.g., of vaccines) so that the experimental condition contains a range rather than a single value on timing, dosage, number of shots (for vaccines). It seems that the usual practice is to decide, on the basis of very small samples, on a single value for each parameter and then test just that value on a much larger sample. But some variation around the chosen value is unlikely to weaken the effect very much, but would tell us how likely it is that deviations from the critical value would matter.

    Such variation is done to some extent with patient variables. Happily, they don’t decide to do the large trial on people age 65-70 only, so they get some idea of how effective the vaccine is at different ages.

    When we have no good evidence about deviations from the protocol, it is no more “ethical” than anything else. It is a matter of decision making under uncertainty. But the uncertainty reduction that results from clinical trials is lopsided, providing much information about some variables (vaccine vs. no vaccine) and little about others.

    • Phil says:

      A modification like the one you describe would presumably complicate logistics, scheduling, and record-keeping, and would certainly complicate analysis…but I agree with you that this is something that should be considered. In the vaccine trials, if the time between doses in the trial varied between, say, 10 days and 20 days, we’d at least know something about the slope near 14 days. It’s very possible that it’s better to wait longer.

  11. Rahul says:

    “because we only have data on the people who get the full dose. We don’t know what happens if you don’t take the full dose, or you take a few days off before continuing”

    So how do they decide on the 30 number? Has the trial concluded that on average 30 has better survival than say 28?

    • Brent Hutto says:

      Most likely the trial concluded that 30 does offers better survival than 0 doses.

      These things can turn into a bit of Catch-22. You do a trial based on 30 doses because you believe (based on pilot studies, theory, whatever) that 30 doses is more likely to produce a benefit than smaller doses would.

      Then once you’ve established that you can save lives with 30 doses while meeting some prescribed safety criteria, it would not be considered ethical to deliberately withhold some portion of the “proven” efficacious dose from some future group of subjects in a reduced-dose trial.

      • Rahul says:

        So wouldn’t it make sense in the trial itself to incorporate some variation? Eg To try say 25, 30, 35 doses?

        Is there a ethical problem there? Typically for such situations how strong is the doctors original belief in the original metric chosen?

  12. Andrew says:

    Jon, Rahul:

    You ask why they don’t incorporate some variation in these trials. It would be fine if they were to do so; as Jon points out, you can still estimate an average treatment effect from such a study. The trouble is that a narrow variation will not give you the leverage to estimate interactions with any degree of accuracy, so you won’t be able to use this study to learn anything useful about relative effects of different versions of the treatment. Remember the rule of 16.

    • Rahul says:

      Is there any way to structure the post trial protocols to incorporate variation to understand these effects?

      Eg following a trial with 30 days should individual docs try variations in a systematic way? Instead of mere post approval surveillance more of a post trial extended trial to tease out variation from a larger sample?

      Or again, would it be ethically unpalatable to try a 25 day treatment on a patient following a 30 day trial?

      Should we pretend we have discovered the optimum ( 30 days) or keep jiggling to see if there’s a better place to be in. I guess it boils down to risk aversion in some sense?

      • Andrew says:

        Rahul:

        I think it does make sense to incorporate variation in the post-trial protocols. Variation is going to happen anyway, so we might as well make use of it. But to come to strong conclusions, you’ll need lots of data or strong prior information. You can’t go with the classical approach of just reporting statistically significant results.

        Regarding your question about ethics: This depends on your prior information. I assume the 30-day rule comes from some scientific model. It could be that, in this model, 25 days is about the same as 30 so the choice is arbitrary. Sometimes it’s possible to gather intermediate data, biomarkers that can allow the scientific model to be explored and tested.

  13. Joshua says:

    Related, Olsterholm discusses delaying 2nd dose. Nothing profound but does introduce the question of how the changed landscape from when the trials were conducted – in that more infectious variants are spreading – comes into play.

    https://nymag.com/intelligencer/amp/2021/03/why-dr-michael-olsterholm-delayed-his-second-vaccine-shot.html

  14. > what progress have we made addressing this uncertainty from both a bioethics, and data collection and design standpoint?
    Not much. A large part of the problem might be due to most researchers not learning much more than cook bookish clinical trial methods. That is they don’t have a deep understanding of the purposes and limitations of the methods but only a surface level knowledge. Or know who to trust on that. That likely includes the individuals you mention in your post.

    Now, the first question to address in a completed study should be what study should be done next, why and how. That includes evaluating all other similar studies (aka meta-analysis), the relevant clinical background knowledge and an informative cost/benefit analysis. If for ethical or logistic reasons the answer is that no additional study can be done or done in time, then usual clinical trial methods should be replaced with “expert judgement”. That varies and is of variable quality.

    We did succeed here with a small non-randomized study that did change clinical practice by arguing a randomized trial would not be feasible given the possible 70% mortality in previously health patients. It was observed to be 35% with treatment. About 5 to 10 years later a group tried to do an randomized trial but shut in down when they could not enroll patients. https://academic.oup.com/cid/article/28/4/800/401565?login=true

    • Rahul says:

      One problem is this intersection between science and freedom. When there’s no consensus even within the scientific community about a certain outcome does it make sense for the regulator to mandate that outcome? e.g. Two dose protocol.

      I think we would be better off (for both science and freedom) if in such situations the regulator allowed public choice. If we were more willing to run experiments of this sort perhaps we would gather more data. Which would then allow for greater public consensus?

      I think a large part of the problem is the regulator being forced (or thinking it is) to pick one option. That compels them to behave they are more certain than they actually are!

      • Brent Hutto says:

        How would you allow “public choice” when there are 10 million doses available and 100 million people who want them?

        Certain or not, the “regulator” has to choose between two undesirable options. No individual member of the public actually has a choice until the allocation policy has been chosen.

        • Rahul says:

          Not that it solves the two dose problem but they should allow the markets to solve the scarcity problem like we do with most other things!

          Here in India both the vaccine manufacturers are complaining that hey have stopped production since they have too many doses waiting to be picked up by the Government. In the millions.

          And yet here I sit barely a few hundred miles away in Bombay waiting for a dose. Furthermore the Government wants to give it out free whereas my willingness to pay would probably exceed a 1000 USD.

          Hardly an efficient outcome. The obsession with centralized distribution and rationing just isn’t working.

          I would rather they allowed the usual market driven medical distribution chains to work and subsidize it for those who actually cannot afford it.

          A two pronged approach of free markets + public services should work much better than the current mess.

          • Agreed, though here in the US I would suggest to ration about 60% of the doses and sell the 40% in a dutch auction style (declining price, you wait and pay when it gets down to what you are willing). The rationing isn’t terrible here but it certainly doesn’t let people who know they are at high risk of contracting it express this information by any means.

            • Rahul says:

              It puzzles me that globally there’s very little discussion of this!

              Are there any nations using a significant component of free market strategy for their vaccine distribution?

              What happened to all the libertarians?!

              • confused says:

                I think it just *sounds* ethically iffy to way too many people for money to play a role, even if it actually makes sense in particular situations.

                This is shaped by public perception and PR/”optics” as well as the most efficient way to do things.

              • Rahul says:

                What’s ironic is that the same nations tolerate nay encourage markets for most other medical interventions, sometimes far more critical too.

                In fact, although covid vaccines have been rationed and centrally distributed gratis, fall sick from covid and bang you are again thrust into the arms of the evil markets for treatment choice.

      • Dale Lehman says:

        Along with Brent Hutto’s point, what do you do when there is no consensus about anything? I am not sure I can think of a single issue where there is a consensus any more – is there a critical mass of agreement/disagreement that would trigger the public choice mechanism? And, what comprises “the scientific community?” Is it by credentials, reputations, citations,…?

  15. oncodoc says:

    Humans are somewhat diverse and outbred. Clinical trials try to overcome this inherent lumpiness in the biological pudding of people by using randomization to steamroll out the differences. This approach has obvious drawbacks, but it is the only that works reasonably consistently. It routinely incorporates such assumptions as the seven day week; there may be advantages to treating some disorders on a six or every eight day cycle. Doses are often multiples of 50 or 500; maybe the right dose of doxorubicin for many people is 47 or 53 mg per meter square. It is only possible to generate data from a small number of trials, and non-seven day based dosing or doses based on some random number have simply not been explored. There is a cultural imperative to push the treatment in my profession; the expression “He is a very aggressive treater” is a term of praise. That’s reality. Every idea can’t be tested.
    On the other hand going outside the limits of what has been established by the slow and painful processes that we have is also difficult. Many brilliant ideas thought up by highly intelligent people have turned out to be wrong. Most clinical trials are not successful. Many successful trials yield very modest results.
    I have treated people outside the parameters of established trials. I consider myself the Babe Ruth of treatment, 714 homeruns, 488 strikeouts (some objective observers might dispute this self-assessment.)

  16. Anonymous says:

    It really seems like medical ethics has very little to do with ethics and everything to do with prestige-conservation and liability transfer.

    • confused says:

      I think the field is very conservative due to past bad examples.

      Whether one thinks this degree of conservatism is warranted in the 2020s depends, IMO, on whether you think current societal structure & technology is different enough from the 1950s and before to rule out those bad examples being repeated. (I do.)

  17. AV says:

    What I read in what you are writing is that the clinician did not follow the feedback of the body to refine – that is to say, over-ride – the rough generalization he had from the trial data, and the resulting missfit resulted in pain.

    That over-ride may well be definable by statistics- your call; I am primed for casuistry

  18. I finished reading Vinayak Prasad’ Ending Medical Reversals. It is a tour de force. I think that one takeaway from the book is that there are some treatments/standard of care are harmful and unhelpful.

    https://www.nytimes.com/2015/11/03/science/book-review-ending-medical-reversal-laments-flip-flopping.html

    This is an uncomfortable hypothesis for patients and physicians.

  19. Eric B Rasmusen says:

    I think the common mentality is that if your confidence level is 94.99%, you can confidently reject that the vaccine works, and if it is 95.01% then you can be absolutely sure it works perfectly. Whether they have low IQ’s or high, a lot of these people have rigid brains and no understanding of what they’re really doing combined with a religious belief that they’re being “scientific” and superior to people who don’t know about the 5% rule.

  20. Anoneuoid says:

    It is kind if a moot point now:

    Findings on B.1.351 are more worrisome in that this variant is not only refractory to neutralization by most NTD mAbs but also by multiple individual mAbs to the receptor-binding motif on RBD, largely owing to an E484K mutation. Moreover, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4 fold) and vaccinee sera (10.3-12.4 fold). B.1.351 and emergent variants13,14 with similar spike mutations present new challenges for mAb therapy and threaten the protective efficacy of current vaccines.

    https://www.nature.com/articles/s41586-021-03398-2

    Not looking good for the current batches of vaccines when it comes to reducing transmission. In a couple months it will be all resistant variants. Looks like ~20% of convalescent sera retained its neutralizing activity though (probably due to non-spike antibodies and vs the S2 region that was mutated to stabilize the vaccines):

    It is also interesting to note that cases such as P7, P10, and P18 have neutralizing antibodies that are essentially unperturbed by the multitude of spike mutations found in these two new variants (Fig. 3b). A detailed analysis of their antibody repertoire against the viral spike could be informative.

    Hopefully the t-cell immunity is more robust so symptom severity is less, but there have already been many reports of more severe symptoms upon reinfection.

    • confused says:

      This seems very overly pessimistic – the mRNA vaccines at least are very strong, so reduced neutralization doesn’t *at all* mean “no longer useful”.

      And in the long run (probably even in the medium term – the high-risk population, at least in the US, will be mostly protected very soon) reducing transmission isn’t what’s really important – reducing severe illness/hospitalizations/deaths is.

      And reports of more severe symptoms upon reinfection don’t mean anything by themselves – of course there will be some. The question is whether *average* severity is less.

      • Anoneuoid says:

        It is the *magnitude* that is concerning. You lose ~10x due to mutations, then 2-5x due to waning after a few months. Then if you limit to one dose that takes another ~10x off the peak value.

        It is obvious that any neutralizing protection will be very short lived. A few months at most.

        And look at the sudden selective pressure in mid-December 2020 here (fig 2): https://www.medrxiv.org/content/10.1101/2021.02.23.21252268v1

        These variants are being driven by pressure to specifically escape the vaccine. This is what happens when you create a monoculture, should have used multi-valent vaccines to begin with.

        • confused says:

          IIRC the evidence now seems to be showing one dose working rather well in practice (not sure how well that correlates to antibody titers, but real-life efficacy is what we mostly care about…)

          Remember antibodies aren’t the only factor in immunity… there are T-cells as well.

          >>These variants are being driven by pressure to specifically escape the vaccine.

          I doubt it. B117 seems to be the one winning out in the US and a number of other places, and it isn’t one of the ones with more vaccine-escape concerns, IIRC.

          • Anoneuoid says:

            Another study from denmark reports 40% more likely for nursing home patients to test positive days 1-14 after first dose of Pfizer. For healthcare workers this was 100% more likely:

            https://www.medrxiv.org/content/10.1101/2021.03.08.21252200v1

            So now we have the clinical trial, UK, Israel, and Denmark all reporting increased rates of illness in the first week.

            • confused says:

              I don’t think it is supposed to be protective that early, so is that especially surprising?

              • Anoneuoid says:

                It is anti-protective for the first week. This has now been reported over and over. People should be warned to be much more careful during this week.

              • confused says:

                It could be, but it could also be reduced caution after getting the shot (although for nursing home patients perhaps this is not the case).

                In any case, the advice is IIRC to retain all precautions until at least 2 weeks after second dose (not sure what it is for the J&J vaccine)…

              • Anoneuoid says:

                It could be, but it could also be reduced caution after getting the shot (although for nursing home patients perhaps this is not the case).

                It is obviously the lymphocytopenia reported in early Pfizer trials and then seen in the RCT. Should I repost this info once again?

              • dhogaza says:

                Earlier you posted:

                “It means people are getting sick and dying in the short term.”

                And I responded:

                “I didn’t see anything about clinical outcomes for those who got a detectable infection during the first two weeks in the Danish study.

                Did I miss that?”

                And your response was:

                “Seems like something worth reporting on.”

                In other words the paper doesn’t report on clinical outcomes, therefore gives no basis for your claim that the one week drop in white blood cell counts is causing people to die.

                Another instance of your citing a paper then making claims unsupported by the paper.

                Tiresome as well as dishonest.

            • confused says:

              I really don’t understand why you are emphasizing any potential doubt/issue with the vaccines. Nothing is 100% perfect, but they seem very good overall – and if the early concerns like antibody-dependent enhancement were real, we’d have seen obvious evidence by now (from natural infection, if nothing else; it’s been a year since the first big spikes, so antibodies should have waned).

              • Anoneuoid says:

                I am just sharing accurate information about what is going on.

              • Joshua says:

                confused –

                > Nothing is 100% perfect, but they seem very good overall

                I thought this might be relevant:

                -snip-

                Data released by the Health Ministry Monday provided a further indication of the effectiveness of the coronavirus vaccine in Israel: Out of those who were tested for the coronavirus at least a week after their second shot, less than 1 percent tested positive, and less than 0.2% developed COVID-19 symptoms.

                The data shows that out of 3,387,340 vaccinated people who had had more than a week pass after receiving their second vaccine dose, only 4,711 were found to be positive for the virus and of those, only 907 developed symptoms, including fever or respiratory problems.

                Israel has almost exclusively been using the two-shot COVID-19 vaccine developed by Pfizer and BioNTech. On Sunday the Health Ministry released data showing that less than 3% of all seriously ill COVID-19 patients in Israel have been fully vaccinated.

                Of the 6,095 coronavirus patients hospitalized in serious or critical condition since the start of Israel’s vaccination campaign, only 175, or 2.87 percent, had received the second vaccination dose, the figures show.

                At the same time, 4,589 patients, or 75% of those in serious or critical condition, had not received a first dose.

                -snip-

                Now of course, it would be different if they were testing people one week after their first shot. It would be interesting to see a dichotomous evaluation of a random sample one week out vs. no vax. But meaningfully controlling for confounds would be awfully tough.

                It would also be nice to know what % of a comparable sample of non-vaccinated were infected and/or symptomatic, but again getting that kind of sample would be tough. The best studies I’ve seen – where they make a serious attempt to control for confounding variables, shows a quite promising comparison of vax vs. non-vax.

                So I’m going to take some solace in 0.2% symptomatic after vaccination.

                https://www.timesofisrael.com/of-fully-vaccinated-israelis-only-0-2-develop-covid-19-symptoms/

              • confused says:

                Factually correct information can still be misleading, if selectively presented. It seems you are only mentioning potential problems and not the *vastly greater* success stories.

              • confused says:

                @Joshua: Yeah, I think everything I’ve seen is significantly better than just “some solace”, it seems extremely promising.

                I wish they would report the time scale after first/second dose for those who were hospitalized, though…

              • Anoneuoid says:

                Factually correct information can still be misleading, if selectively presented.

                Correct. Just look at the quote Joshua posted for an example of this.

                at least a week after their second shot… who had had more than a week pass after receiving their second vaccine dose

                They should not leave out that in the first week all evidence and reason (science) now says you are *more susceptible*.

                Then there are the issues of waning and new strains. I personally hope the news just stops talking about covid altogether no matter what happens but it is obvious that people getting infected during that first week are getting sick and incubating resistant strains.

              • Dale Lehman says:

                Anoneuoid
                Now you have me confused, not the “confused” persona/author. You appear to be saying that the first week after the 2nd dose is an especially vulnerable time. Yet the study you list above concludes “The results were promising regarding the VE both within and beyond seven days of second vaccination with the BNT162b2 mRNA Covid-19 Vaccine currently used in many countries to help mitigate the global SARS-CoV-2 pandemic.” So, are you referring only to the period after the first dose? Or are you disagreeing with the study you cited? I’m just trying to understand and the article you cite and your last comment appear to be contradictory.

              • Anoneuoid says:

                You appear to be saying that the first week after the 2nd dose is an especially vulnerable time.

                No, there is no evidence for that.

                So, are you referring only to the period after the first dose?

                Yes, there is a lot of evidence for this.

              • Anoneuoid says:

                I’m just trying to understand and the article you cite and your last comment appear to be contradictory.

                Simply look at “0-14 days after first dose” in table 2 from the paper: https://www.medrxiv.org/content/10.1101/2021.03.08.21252200v1

              • dhogaza says:

                “Now you have me confused, not the “confused” persona/author. You appear to be saying that the first week after the 2nd dose is an especially vulnerable time.”

                Nah, he’s talking about the first week after the first dose.

                Note that the protection given afterwards, including after the second dose, swamps whatever minor increase there might be in the IR in that first week.

                Overall, the vaccines work, and work well. The studies he points to don’t argue that they don’t, not at all.

              • Anoneuoid says:

                Healthy adults 18 to 55 years of age or 65 to 85 years of age were eligible for inclusion.
                […]
                The largest changes from baseline in laboratory values were transient decreases in lymphocyte counts, which resolved within 1 week after vaccination (Fig. S3) and which were not associated with clinical manifestations.

                https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583697/

                As specified in the protocol, suspected cases of symptomatic COVID-19 that were not PCR-
                confirmed were not recorded as adverse events unless they met regulatory criteria for
                seriousness. Two serious cases of suspected but unconfirmed COVID-19 were reported, both in
                the vaccine group, and narratives were reviewed. In one case, a 36-year-old male with no
                medical comorbidities experienced fever, malaise, nausea, headache and myalgias beginning
                on the day of Dose 2 and was hospitalized 3 days later for further evaluation of apparent
                infiltrates on chest radiograph and treatment of dehydration. A nasopharyngeal PCR test for
                SARS-CoV-2 was negative on the day of admission, and a chest CT was reported as normal.
                The participant was discharged from the hospital 2 days after admission. With chest imaging
                findings that are difficult to reconcile, it is possible that this event represented reactogenicity
                following the second vaccination, a COVID-19 case with false negative test that occurred less
                than 7 days after completion of the vaccination series, or an unrelated infectious process. In the
                other case, a 66-year-old male with no medical comorbidities experienced fever, myalgias, and
                shortness of breath beginning 28 days post-Dose 2 and was hospitalized one day later with
                abnormal chest CT showing a small left-sided consolidation. He was discharged from the
                hospital 2 days later, and multiple nasopharyngeal PCR tests collected over a 10-day period
                beginning 2 days after symptom onset were negative. It is possible, though highly unlikely, that
                this event represents a COVID-19 case with multiple false negative tests that occurred more
                than 7 days after completion of the vaccination regimen, and more likely that it represents an
                unrelated infectious process.

                Among 3410 total cases of suspected but unconfirmed COVID-19 in the overall study
                population, 1594 occurred in the vaccine group vs. 1816 in the placebo group. Suspected
                COVID-19 cases that occurred within 7 days after any vaccination were 409 in the vaccine
                group vs. 287 in the placebo group. It is possible that the imbalance in suspected COVID-19
                cases occurring in the 7 days postvaccination represents vaccine reactogenicity with symptoms
                that overlap with those of COVID-19. Overall though, these data do not raise a concern that
                protocol-specified reporting of suspected, but unconfirmed COVID-19 cases could have masked
                clinically significant adverse events that would not have otherwise been detected.

                https://www.fda.gov/media/144245/download

                The odds of testing positive by interval after vaccination for BNT162b2 compared to those unvaccinated was initially analysed for the full period since the roll-out of the BNT162b2 vaccination programme on 8th December 2020 (supplementary table 2, supplementary figure 2). During the first few days after vaccination (before an immune response would be anticipated), vaccinated individuals had a higher odds of testing positive, suggesting that vaccination was being targeted at those at higher risk of disease.

                […]

                The odds of testing positive among vaccinated individuals increased during the early period up to days 7-9, reaching 1.48 (95%CI 1.23-1.77). The odds ratios then began to decrease from 10-13 days after vaccination, reaching 0.41 (95% CI 0.32-0.54) in the 28-34 day and remaining at a similar level from 35 days onwards.

                https://www.medrxiv.org/content/10.1101/2021.03.01.21252652v1

                Why aren’t people being told to act as if they are immunosuppressed during that first week?

              • dhogaza says:

                “They should not leave out that in the first week all evidence and reason (science) now says you are *more susceptible*.”

                Which means diddly over the long term.

                People are warned to continue precautions until two weeks after their second vaccine, and the fact that there might be an increased risk of infection for the first week after doesn’t change that.

                The Denmark and Israel papers show very high overall efficacy, closely matching the trial results for Pfizer.

              • Anoneuoid says:

                Which means diddly over the long term.

                It means people are getting sick and dying in the short term. The long term consequence is that they are near perfect incubators for new strains.

                People are warned to continue precautions until two weeks after their second vaccine, and the fact that there might be an increased risk of infection for the first week after doesn’t change that.

                Immunocompromised people need to take extra precautions. People should be told to be extra careful during that first week (even take off work, etc). Basically act like you tested positive for covid.

                So once again we have a simple, safe method of saving lives that is not being used.

              • confused says:

                I doubt incubating new strains will matter at this point, given the vaccination rates and the time it would take for a new strain to become common. The window probably closed a month or two ago for anything to become common before the end of the pandemic.

                (A true vaccine escape strain – not just somewhat-reduced neutralization capacity as in the B.1.351, but actually immunologically naive again, would change that, but I am *extremely* skeptical of that being a thing that can plausibly happen, as it doesn’t seem to happen with other respiratory viruses.)

              • Joshua says:

                > I tend to agree w @CT_Bergstrom that virus unlikely to run out of evolutionary “space” for antigenic change. This doesn’t happen much for flu or CoV-229E, so doubt it will for SARS-CoV-2. That said, two things that could somewhat slow antigenic evolution in future…

                https://mobile.twitter.com/jbloom_lab/status/1369080278312886273

                > We see high neutralizing activity against all strains tested, including P.1 that is spreading so rapidly in Brazil. While activity is diminished against the B.1.351 strain from South Africa, it is still very impressive—and higher than mean activity against wild type after 1 dose.

                https://mobile.twitter.com/CT_Bergstrom/status/1369123248470827016

              • dhogaza says:

                “It means people are getting sick and dying in the short term.”

                I didn’t see anything about clinical outcomes for those who got a detectable infection during the first two weeks in the Danish study.

                Did I miss that?

              • dhogaza says:

                “(A true vaccine escape strain – not just somewhat-reduced neutralization capacity as in the B.1.351, but actually immunologically naive again, would change that, but I am *extremely* skeptical of that being a thing that can plausibly happen, as it doesn’t seem to happen with other respiratory viruses.)”

                The premise is that the lower white blood cell counts make it easier for people to become infected before the antibody response builds to any reasonable level.

                So it’s hard to see why an antibody-escaping strain would be selected for during that short period of time in the first place. Sure, such a mutation might happen, but unless it was also more efficient at reproducing in an environment where antibodies are absent there’s no reason for it to reproduce in large numbers. If it were less efficient the “normal” virus would out reproduce it anyway.

                And … there’s really no difference in the lack of selection pressure compared to a situation where the rate of infection over the first week or so isn’t increased. A relatively small number of additional people falling ill in an antibody-free environment.

                All this on top of your skepticism.

              • Anoneuoid says:

                I didn’t see anything about clinical outcomes for those who got a detectable infection during the first two weeks in the Danish study.

                Did I miss that?

                Seems like something worth reporting on.

                So it’s hard to see why an antibody-escaping strain would be selected for during that short period of time in the first place.

                Might be hard for people who don’t use science to see, but that is what happens in immunosuppressed people. It is already happening:
                https://www.medrxiv.org/content/10.1101/2021.02.23.21252268v1

                This really feels like Feb 2020 all over again in every way. But as I said already, there is no way a no variant can be worse than the early intubation, OD-ing on HCQ, and sending infected into nursing homes. So it won’t be that bad. I hope the news just ignores it so we don’t get a repeat of that.

              • Joshua says:

                > Whatever SARS-CoV-2 variants eventually summit that peak could be a considerably bigger problem for us than any variants that we currently know in that they might have any combinations of increased transmissibility, altered virulence and/or increased capacity to escape population immunity.

                I’m going to try to unread that.

              • dhogaza says:

                “Might be hard for people who don’t use science to see, but that is what happens in immunosuppressed people. It is already happening”

                One of us doesn’t understand how the word “hypothesis” is used in science. As found in the term “chronic-illness-emergence-hypothesis”. The discussion in the paper makes clear the fact that they are proposing this as a hypothesis, nothing more.

                And the hypothesis was developed in regard to chronic covid illness caused by the inability of the immunocompromised individual’s body not being able to clear the virus for months, not a week long suppression of white blood cells followed by a rapid increase in antibody levels, as is seen in those who get their first shot of an mRNA vaccine.

                This presents a very different host environment for the virus than they are discussing, and there is no basis for you to extrapolate their hypothesis to this very different host environment. The timescale is vastly different, the drop in white blood cells is transient, most will have healthy immune systems without even considering the immune response to the vaccine.

                As they say:

                “By allowing the accumulation of larger combinations of epistatically interacting mutations and facilitating better exploration of local fitness landscapes within individual patients, chronic infections could have enabled the serendipitous discovery of new peaks on the global fitness landscape”

                Chronic infections. Chronic. Their hypothesis simply doesn’t apply to the physiological response to the first shot of an mRNA vaccine.

                Go back and read the paper more closely.

                Just between you and me, I actually read that paper when it first showed up …

              • Anoneuoid says:

                Just between you and me, I actually read that paper when it first showed up …

                Look at figure 2C. What method did they use to choose the date for that big red line with a gap in mutations until mid-December? Think critically.

              • confused says:

                >>> I tend to agree w @CT_Bergstrom that virus unlikely to run out of evolutionary “space” for antigenic change. This doesn’t happen much for flu

                I am not sure they are talking about exactly the same thing, because IIRC the flu pandemics recent enough to have known origins come from *zoonotic* events, not from mutation within humans.

                I would like to see evidence of any disease, anywhere, circulating within humans mutating to cause a new pandemic/epidemic (as opposed to starting as zoonoses, or contact between two previously separated human populations e.g. smallpox in the New World) before I start worrying about that.

              • Joshua says:

                confused –

                > I am not sure they are talking about exactly the same thing,

                Yes, but I thought it was related, and interesting.

              • confused says:

                >>Yes, but I thought it was related, and interesting.

                Oh, it is, sorry; I thought that was a direct counterargument against my idea that new variants (as opposed to B117, and maybe B.1.351, which had significant time to spread before vaccination was common) won’t make much of a difference.

            • Navigator says:

              Anon,

              It’s just a function of both groups having high chance of getting infected (HC workers and nursing home).

              There’s nothing special about the vaccine making you more susceptible to infection, compared to not getting vaccinated.

              A lot of those studies are just documenting noise. Remember that in the original trials that ‘magic’ 95% efficacy is derived from 8 vs. 162 infections in vaccine vs. placebo arm.

              Vast majority (heck, almost all) of the participants in both arms didn’t get covid.

              The assumption that participants in both arms somehow had the same chance of exposure for weeks on end is the mother of all assumptions.

              What matters is that immunity takes time to build and one dose might as well be enough given enough time.

              All this dose-response stuff in medicine is quite arbitrary. Various intermediate points never get tested.

              I always get half a dose of Advil if I need, and it works.

              Take it from former big pharma guy:

              https://www.youtube.com/watch?v=lXK2j1Qxb4U

              • Joshua says:

                Intersting. Thanks for that clip.

              • Anoneuoid says:

                There’s nothing special about the vaccine making you more susceptible to infection, compared to not getting vaccinated.

                Yes, there is:

                Healthy adults 18 to 55 years of age or 65 to 85 years of age were eligible for inclusion.
                […]
                The largest changes from baseline in laboratory values were transient decreases in lymphocyte counts, which resolved within 1 week after vaccination (Fig. S3) and which were not associated with clinical manifestations.

                https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583697/

                I guess now lymphocytopenia does not lead to increased chance of infection? Even though now we have seen increased infection rates multiple times including in the RCT?

                You can’t just ignore decades of science because of covid.

          • dhogaza says:

            “Look at figure 2C. What method did they use to choose the date for that big red line with a gap in mutations until mid-December? Think critically.”

            In other words you can’t defend your claim that their hypothesis is fact, and despite being based on chronic infection it is equally factual in a host environment where immunosuppression consists simply of lower white blood cell counts and only lasts about a week.

            I’d expect someone whose vision is based on science to be above a simple Gish Gallop.

            • Anoneuoid says:

              I was just checking whether you could go deeper than parroting back what they wrote. I’ve been in many journal clubs filled with that type of shallow thinking mostly driven by the need to “get back to work”. This breeds an anti-scientific authoritarian mode of thinking. Nullius in verba.

              You read the paper but did not understand it.

              • Rahul says:

                For completeness sake, what’s the counterfactual?

                Someone who sees conspiracies everywhere?

              • Anoneuoid says:

                For completeness sake, what’s the counterfactual?

                Someone who sees conspiracies everywhere?

                That the standard behavior I saw all the time when doing medical research continues to be standard. Reviewers telling you to leave out inconvenient data, excuses to include/exclude various points, once a paper is published the interpretation is accepted to be correct by default, p-hacking “because I need to survive”, etc.

                I like how using science and thinking critically is now a “conspiracy theory” though. Western civilization has a bright future if this continues.

                I mean look at the Denmark paper. It is right in your face. Why do they not mention that result in the text? Did they not see it in their own table?

              • Joshua says:

                Anoneuoid –

                > Reviewers telling you to leave out inconvenient data,…

                OK. Just one more (Andrew, I promise).

                A lot of these are preprints.

            • dhogaza says:

              “I was just checking whether you could go deeper than parroting back what they wrote.

              You read the paper but did not understand it.”

              What you are really saying is that they wrote the paper and didn’t understand it …

              You do that constantly with the papers you cite.

  21. Anoneuoid says:

    Look again at this:

    Simply look at “0-14 days after first dose” in table 2 from the paper: https://www.medrxiv.org/content/10.1101/2021.03.08.21252200v1

    They saw a statistically significant 2x increase in infections during that first week for healthcare workers and 40% increase for nursing home residents, yet the authors do not mention it in the text. Can you apply critical thinking to offer an explanation for why that would be?

    • confused says:

      Because people would take it out of context to make the vaccine sound dangerous, and because it’s unimportant if people maintain measures until 2 weeks post-second-dose as recommended?

      I just got the first dose today; even if my risk is doubled for the next few days, the fact that I’ve successfully avoided it for a year implies that my base-rate risk of getting it in the next few days is not very high, so doubling it is not that much.

      (And do we really know this is not at least partially due to reduced carefulness?)

      • confused says:

        IE… double risk of getting it for one week, then vastly reduced risk for the next year (and maybe reduced risk of severity forever, T-cells may persist for ages as they did for SARS-1), is still an incredibly clear win. Total risk is still vastly reduced.

        • dhogaza says:

          And the rate of vaccination is increasing as the rate of new infections is steadily decreasing.

          Where I live the new case rate is lower than it’s been since May. About 30 cases per day in a county of 434,000. Obviously there are more cases than those that are confirmed, but still, the risk of exposure is low during that first week after shot one even if one does nothing to protect themselves. And those who get vaccinated are those most likely to be protecting themselves, so seriously, the risk is low.

          Then we have the problem that he’s conflating a host environment where there’s a possible short-term decrease in protection followed by a steep increase in antibody production with a host environment associated with chronic covid caused by long-term immunosuppression. He is claiming that they are evolutionarily equivalent. And worse, he takes a proposed hypothesis as being an established fact.

          • confused says:

            Yes, exactly. The decline may be slowing, but the numbers in the US over the last six weeks have really been better than I hoped – two months ago I’d expected the B117 variant to be having much more of an impact by now (nearly two weeks into March) than it seems to have had.