This is promising technology, but the words "just barely statistically significant" should probably be in the first paragraph of articles covering this - not halfway down the article.
"Just barely statistically significant" but the MLE is a 6x reduction in hospital visits. There's huge potential here, but our ability to know has been hampered by study size.
That's not quite the right takeaway. That 6x reduction is dependent on the p-value, which in turn is dependent on the sample size. The larger the sample, the smaller the p-value, and that 6x reduction will likely shrink as well. It's extremely rare for a treatment in medicine to have a 6x benefit.
> That 6x reduction is dependent on the p-value, which in turn is dependent on the sample size
No, the 6x reduction MLE is -not- dependent on the p-value, and this shows a fundamental misunderstanding of the statistics. That said, the overall distribution of possibilities skews on the "lesser effect" side, so if you had to guess which way the estimate would move with another trial, you're more likely to get a smaller effect than a larger one.... 6x is still the most likely single value.
> It's extremely rare for a treatment in medicine to have a 6x benefit.
All kinds of drugs and treatments for acute disease have a > 6x benefit. We have plenty of conditions that have a horrible prognosis untreated and great outcomes treated.
Have a bad bacterial infection? Odds are abx will clear that right up and you'd die otherwise. Active TB has a ~60% death rate within 5 years untreated, while with normal treatment regimens only has a relapse (not death) rate of a few percent in that 5 year period. Most vaccines have high efficacies. Standard treatments can prevent the vast majority of malaria deaths.
That's for one of several results, and the whole point of those words appearing is to imply that it contrasts with the other results.
I mean, arguably reporting on things at this stage is super premature, the whole article shouldn't exist, we shouldn't be reading it, the whole news cycle is garbage, blah blah blah rant rant rant.... but it would be absurd to headline the article with "the least significant, of several significant results, was only barely significant".
They didn't tell us how many patients. Could be important, could be noise. Also, there were two serious reactions to infusion of one of the drugs.
It's progress. A few months ago nothing worked. It was just ventilators, supportive treatment, and wait to see who survived. Now, some treatments sort of work. Management of the disease is becoming possible.
In this study, the drugs were given early, and to patients who were not sick enough to require hospitalization. Not clear if this helps with the more serious cases.
Sounds like Trump got a similar cocktail from a different company. The speed of his recovery and the fact that him having Coronavirus isn't even part of the news cycle anymore seems like a strong indicator that the treatment is probably a game changer.
A single person's progression who was in every single category of death susceptible patients tells us more than the recovery of an otherwise healthy person's progression.
The average death rate at his age is 4%. And I think he has got average amount of problems and obesity at his age in US, at least no very big disease and not in the higher end of obesity.
This is a tautology, and in no way addresses the point that absolutely nothing is learned about the efficacy of one of the drugs he took, by looking at a single data point.
Okay, here is the data point: If you get treated by some of the best doctors your country has to offer in an absolute state of the art facility in record time (i.e. almost no delay between outbreak of covid and detection) the given drug cocktail was effective (if we assume they don't lie about Trumps health. In the footage on his return to the white house he didn't look healthy at all).
I'd argue that this certainly is a data point. Just not a very useful one.
Well, it might not, but the article is about Eli Lilly saying their studies say the drug is effective, and the anecdotal evidence that Trump took it and recovered very quickly seems to add credence to that claim.
People love to hate on anecdotes, but they have their place.
Why are we assuming he’s out of the woods and “cured”? All of the medical experts seem to indicate that 7-10 days is when the real complications begin. The earliest we know him to be infected is Wednesday of last week. He’s just coming up on the 7 day threshold.
Let’s at least wait through the weekend before we declare him “cured”.
I don't understand how one person treated with something, just because they recovered, makes this a game changer. I also don't get why it would take "curing" the president to know of a specific cocktail that works.
I kinda am losing all faith in all things medicine if we've had experience, as a whole, to try to treat 36 MILLION people with this issue and one specific treatment for one specific person, who happens to survive like 35 MILLION others so far. And THATS the winning combo, And it happens to be our president. It's like the other 35 MILLION was just junk data or something.
There are thousands and thousands of people in the biomedical field all around the world working furiously behind the scenes at the moment on this problem.
Unfortunately, there is no single mouthpiece for this effort so people aren't aware of how many people are pulling out the stops, but despite how bleak things may look there are a lot of MDs and PhDs and MD/PhDs trucking away trying to find a way out of this thing.
Ok, fair enough. I dunno if I'm 100% on this, but I'll argue it:
It's important to keep in mind the difference between clinical and basic lab research.
Basic lab research is done in a sort of a closed system. There's a small group of people (grad students, post-docs) working on a limited set of projects. They all have their individual lab notebooks that are property of the lab. Nobody has to disclose anything to anybody, except the IRB and whoever is handing out grant money. The head of the lab, well their entire career depends on what that...lab...does... There is no plan B, other than teaching at a liberal-arts school or community college.
Most clinical researchers aren't as against-the-ropes in terms of their career as PhDs, because they're doctors and they can just go do medicine. Wups, my clinical study didn't work out, guess I'll go be absolutely.........fine..........
Plus, it's harder to keep things secret in a hospital. There's a lot more variables, and it's not as closed a system as a lab.
So for the COVID stuff, you have both MDs/DOs and PhDs working alongside each other in multidisciplinary teams. Thus, information is not as readily concealable and so there's less paranoia because....well, what's the point?
The relevance is that the President got wall to wall media coverage for being sick. And his is in a demographic (old, overweight, male) that puts him at an extremely elevated risk for serious illness.
Doctors will do their job and scientists will do their job, and in the end decisions will be made based on the results of studies.
That doesn't negate the enormous amount of positive press that this event will give to the treatment.
Either way, it should be a signal that we are getting much better at treating the illness. Back in April, Boris Johnson, who is basically a Trump equivalent, but 20 years younger, spent a week in the hospital in very rough shape.
The news on Cornavirus is in trending significantly in the positive direction, which is really all that matters.
> Positive in terms of increasing case numbers, yes.
As the number of people I know who have caught it grows, I have to say I don't really see that as a negative thing.
Most of the new cases are in the young-adult demographic.
Almost universally they suffer no long term complications and the most unpleasant part of the sickness is being confined to their home for a week and a half.
Number of confirmed cases is the wrong metric.
We know very well by now who is at elevated risk.
If you are not in the elevated risk category, and you are able to avoid those who are at elevated risk, then there is very little for you to worry about.
>Almost universally they suffer no long term complications and the most unpleasant part of the sickness is being confined to their home for a week and a half.
Citation please.
As a relatively young person suffering from the long-term consequences of this disease, I am infuriated whenever anyone says something so false.
> ... I am infuriated whenever anyone says something so false.
Citation please.
Is it actually false? Your one case does not a fact make. What percentage of confirmed cases in people under the age of, say, 40, result in long term complications?
Edit: Corrected punctuation and replaced "statistical fact" with just "fact".
Percentage of confirmed cases is the wrong statistic to be looking at here. Because a lot of these cases aren't even being tracked due to not having life threatening symptoms, but never the less seem to result in long-term symtoms that have a significant impact on people's lives.
Why would there be positive press for this treatment, the President was treated by a different therapeutic from another company. From the article "The results also appear roughly similar to those Regeneron presented last week of its own cocktail of two monoclonal antibodies. Last Friday, President Trump was treated with the Regeneron monoclonal antibodies."
In Trump's video statement he said, "I was treated with Regeneron. Eli Lilly has something very similar they are working on as well. They call them therapeutics, but I view them as honestly a miracle."
However, he did end up in a hospital, on oxygen, and they gave him dexamethasone (which isn't something they do just for fun). So it's not a wonderful advertisement for reducing hospitalization, really (many people who end up in hospital wouldn't need dexamethasone).
It could just as well be a strong indicator that his initial viral exposure was small, and/or that being detected early, treated quickly and exceptionally well by a dedicated team matters.
Only problem, I suspect, is it's super expensive and hard to produce in the large amounts required. So not as much of a game changer as we'd like. Still should save a few lives.
I am lucky enough to have solid insurance provided by work and I had to fight hard to get a monoclonal antibody covered. One that was actually approved by the FDA. The cost if you can't get insurance to cover it is ~$3,000 per dose.
Yup, which lead to early treatment. Most people start treatment when the illness has progressed far. Hospitals generally withhold treatment to see if patients will recover by themselves because they can't risk "waste" of medicine and filling up hospital beds. So most people are sent home unless it's really bad. Trump started getting treatment from the very moment he tested positive.
relying on a PR team for data (who has a perfectly reasonable national security reason for lying about that data) and then using a single point of data to make claims is just so antiscience I can't even.
It's completely predictable that the expensive drugs that Trump got (the monoclonal antibodies & Remdesivir) dominate the news cycle, while the cheap ones don't. From, the Physician to the President's report on October 2nd [0]:
>Following PCR-confirmation of the President’s diagnosis, as a precautionary measure he received a single 8 gram dose of Regeneron’s polyclonal antibody cocktail. He completed the infusion without incident. In addition to the polyclonal antibodies, the President has been taking zinc, vitamin D, famotidine, melatonin and a daily aspirin.
If there's a game changing drug for COVID-19 in there I'd say it was vitamin D.
We covered the Spanish randomized open label, double-masked clinical trial of vitamin D just over a month ago. [1][2]
>“Of 50 patients treated with calcifediol, one required admission to the ICU (2%), while of 26 untreated patients, 13 required admission (50%) p value X2 Fischer test p < 0.001.”
The Internet Book of Critical Care is a collaborative effort by front-line docs to share information about promising therapies and approaches to COVID.
It's really interesting, and broken down by bullet points.
Check it out, and get an idea of how actual doctors in the field are approaching this thing.
Neither is anyone at my academic teaching hospital.
A lot of really smart people with decades of experience in the field, and a direct clinical role have collected a variety of approaches that seem to work. Unfortunately, none of them have characterized Vit D as a 'game changing drug.'
I think it might be wise to hold off on phrases like 'game changing' with regards to Vitamin D.
Not to say that it may not eventually play a role as part of a multifaceted approach.
Re: "game changer", I was referencing the comment by war1025 that polyclonal anti-bodies were a game changer.
>Sounds like Trump got a similar cocktail from a different company. The speed of his recovery and the fact that him having Coronavirus isn't even part of the news cycle anymore seems like a strong indicator that the treatment is probably a game changer.
>A lot of really smart people with decades of experience in the field, and a direct clinical role have collected a variety of approaches that seem to work. Unfortunately, none of them have characterized Vit D as a 'game changing drug.'
Sorry - I'm more impressed by a single randomized open label, double-masked clinical trial than I am by argument by authority. Perhaps we can check back here in a couple of years time ...
I can't help remembering how actual doctors in the field were telling us back in February to "get a flu shot", or "masks only work for doctors who've been trained to put them on properly". I'm so happy that I'd already purchased my N95 masks in January while you guys were asleep.
I advise you to scope out the definition of a pilot trial. Here's a cool one I found:
"A pilot trial is a small study conducted to help design and assess the feasibility of doing a larger, full‐scale trial. They also investigate whether the methods and procedures are able to obtain the data that is needed to answer the question that will be addressed in the larger study."
"Clinical trials are research studies performed in people that are aimed at evaluating a medical, surgical, or behavioral intervention. They are the primary way that researchers find out if a new treatment, like a new drug or diet or medical device (for example, a pacemaker) is safe and effective in people. Often a clinical trial is used to learn if a new treatment is more effective and/or has less harmful side effects than the standard treatment."
Getting a flu shot is important. Please get yours this season so we can help reduce the spread of yet another deadly respiratory virus that kills thousands of people each year.
There was a lot of debate about masks. As you can recall, a lot of frontline health professionals were dying because of a lack of PPE while carrying out
incredibly risky procedures like intubation.
Gondi, S., Beckman, A. L., Deveau, N., Raja, A. S., Ranney, M. L., Popkin, R., & He, S. (2020). Personal protective equipment needs in the USA during the COVID-19 pandemic. The Lancet, 395(10237), e90–e91. https://doi.org/10.1016/s0140-6736(20)31038-2
I'm happy that you have your N95 masks to keep you safe at Trader Joes (where all of us normal folks have been well-served with cloth masks and social distancing) because god forbid an emergency room nurse or doctor needed N95-level protection while securing a patient's airway after they stop breathing.
I don't know what you're implying by the phrase 'argument by authority,' but we're talking about people who have spent their entire careers in the field of medicine. Normally we call those people 'scientists' and 'experts.' I'd trust Dennis Richie to know a thing or two about C, and if I wanted to know a little something about algorithms I wouldn't be done a disservice by chatting with Donald Knuth.
Edit: I wrote this on my other comment too, but I wanted to put it here to make sure you saw it:
First of all I'd like to preface this by saying that everything I write is with a light heart, and I'm not actually 'angry' or feeling any sort of ill will towards you. Everything is weird now with COVID, and sometimes when we say stuff on the internet it might sound more aggressive than it is intended to. So, no matter what our different opinions are I love you dude, and if we were in person I'd buy you a beer.
>Getting a flu shot is important. Please get yours this season so we can help reduce the spread of yet another deadly respiratory virus that kills thousands of people each year.
It turns out that masks are far more effective than flu shots, so no, I'm not going to get a flu shot. Anyway, IIRC, "kills thousands of people each year" is a statistical projection that doesn't actually stand up to scrutiny. Certainly, it's nothing like COVID-19.
>There was a lot of debate about masks.
There was a lot of misinformation spread because of the failure to stockpile PPE. That misinformation is still doing harm now because the MAGA folks are running around saying "masks don't work"
>I don't know what you're implying by the phrase 'argument by authority,' but we're talking about people who have spent their entire careers in the field of medicine. Normally we call those people 'scientists' and 'experts.'
Unfortunately, medical experts credibility is now shot by spreading false information about masks, and by downplaying the risk of COVID-19 in January and February by telling everybody to get a flu shot. Then I wonder how many people died on ventilators when intubated on MAX ..
As a group you're weren't operating at the level of Dennis Richie or Donald Knuth, so you have work to do to regain credibility.
In fact, you're still not now. You should focus less on evidence-based medicine and more on risk asymmetry. Mask wearing (even of cloth masks) had very little downside and a potentially huge upside. But we had to wait for evidence. The same is true of vitamin-D now. Look for low-risk interventions. If we don't have the resources to mass test the at-risk population, we should encourage those on poor diets to take 1000IU a daythis winter. But we will have to wait until next year for evidence.
Wait, you do understand that people are saying to get the flu shot so people don't get the flu, right? They're not saying that the flu shot will protect you against COVID.
Where do you get your data about annual influenza deaths? If you have a good source, I'm willing to take a look.
It's important not only so you don't get sick, but also so you don't spread it to others who may have a weaker immune system. We're all in this together.
Please don't lump all health care personnel in with political appointees in Washington D.C.
Donald Knuth is a computer scientist, not the president's politically-appointed personal pet computer scientist.
>Wait, you do understand that people are saying to get the flu shot so people don't get the flu, right?
For sure, but I don't happen to agree. It was on the news here in Japan this morning - flu cases have pretty much disappeared this season - presumably because everyone is wearing masks.
>Where do you get your data about annual influenza deaths? If you have a good source, I'm willing to take a look.
I can look for it, but IIRC the several 10,000 annual influenza deaths are a statistical projection. There was an article somewhere from someone in ER during the peak of the COVID-19 deaths saying they had pretty much never seen an actual influenza death - and that was the experience of other people in ER - so there was a mismatch between the statistical projection and lived experience.
>It's important not only so you don't get sick, but also so you don't spread it to others who may have a weaker immune system. We're all in this together.
The best way to do that is to wear masks. Here in Japan - nobody here ever said that "masks don't work for non-medics who haven't been trained to put them on properly". So we don't now have the problem with lots of MAGA folks running around saying "masks don't work".
It would be wonderful if we were anywhere near as diligent with masks as folks in Japan have been.
Unfortunately, masks became a political issue here in a way that probably had nothing to do with those dumb CDC press releases. Masks were cleverly and intentionally linked to a sentiment of 'freedom' and 'fascism' in an almost astonishing way.
This kind of thing doesn't even raise eyebrows here anymore:
I don't know how much of it you've seen in Japan, but this country is divided, scared, and hopeless in a way that nobody I've talked to can claim to have experienced in their lifetime. People's family members are dying, people are losing their jobs, people are being evicted, people are losing their businesses, politicians are locked in a geriatric MMA grapple, and there's no vision for how we're getting out of this.
Actually, I'm generally pro-freedom where there is no obvious victim. But that's not true in this case. The way I see it is you can suffer the more modest loss of freedom of mask wearing now. Or you can ignore that and have lockdowns imposed on you later.
>Unfortunately, masks became a political issue here in a way that probably had nothing to do with those dumb CDC press releases.
You want to believe that, but I think in your heart you know that is not true. Those messages seeped into the public consciousness. I'd be astonished if they're not being cited by MAGA et al against you now.
Generally, if you treat people like children, like the CDC did, they won't respond by behaving like adults.
That trial has several issues. Everyone is patiently awaiting larger RCTs to further understand if Vitamin D does anything as a prophylactic. It's been shown to not be helpful in severe cases.
>It's been shown to not be helpful in severe cases.
That's a fairly strong assertion! Stronger than, "there is no evidence that is helpful in severe cases" for example.
You wouldn't happen to have a reference to back it up by any chance?
Anyway, I'm wondering why vitamin D is held to a higher standard than the polyclonal antibodies or Remdesivir. Where is the evidence that they're helpful in severe cases?
By the way, I'm not advocating for long-term, high-dose consumption (say over 2000 IU) consumption of vitamin D.
Deva Boone (devaboone) 's blog points out that this can lead to dangerously high calcium levels and has been covered on here several times recently [0][1]:
>Eventually we worked out what happened with Shannon: In 2013 she was diagnosed with mild osteopenia, a thinning of the bones that can be a precursor to osteoporosis. Her Vitamin D was low at the time, so her physician started her on over-the-counter Vitamin D supplementation at 5000 international units (IUs) daily. Five years later, she was still on this dose, and her blood Vitamin D level had risen to 79 ng/ml. This level is within what many labs call the normal range, between 30 and 100 ng/ml, but levels above 70 are almost always a result of high dose supplementation, and I have seen toxicity with levels between 70 and 100 ng/ml. (A better “normal range” based on what I have seen would probably be between 30 and 60.) Vitamin D builds up over time, so the longer someone is on a high dose, the more likely she is to develop toxicity. Shannon’s calcium levels began rising in the fall of 2018, when her severe symptoms developed.
What we should be doing now is mass-testing the at-risk population to identify those people with blood levels below 30 ng/ml and then do what is necessary to bring them up into the 30 to 40 ng/ml range. Ideally that could be done with sunlight, or food high in vitamin D - for example oily fish, liver, dried-shitake, ... But for the at risk demographic, in practice one would probably need moderately high-dose supplements, combined with monthly testing until they're above 30 ng/ml, followed by a switch to a lower-dose maintenance dose.
"Isn't there at least enough evidence at this point to recommend it for everyone with Covid?
No, not really. There is suggestive evidence from a small pilot study. There is likely an effect, though we can't yet say how large that effect is. A few doses of high-dose Vitamin D are probably not going to hurt, but there are harms to massive doses of Vitamin D - and if we give it to everyone indiscriminately we will see more of those. Also remember that younger patients were excluded from the assessment of mortality risk in the third study - because no one under 40 died in their study, despite the fact that most of them were deficient in Vitamin D."
It's complicated. There's a lot of nuance, and there's a very real likelihood that Vit D deficiency may just be a proxy for an unhealthy lifestyle.
>there's a very real likelihood that Vit D deficiency may just be a proxy for an unhealthy lifestyle
Seriously! You think that it might be possible that vitamin D deficiency doesn't exist at all and that people used to get rickets because of an unhealthy lifestyle. You're kidding right ...?
In case, it's not clear, I repeat:
>By the way, I'm not advocating for long-term, high-dose consumption (say over 2000 IU) consumption of vitamin D.
What I am advocating for is:
>What we should be doing now is mass-testing the at-risk population to identify those people with blood levels below 30 ng/ml and then do what is necessary to bring them up into the 30 to 40 ng/ml range. ...
Actually, I agree that the evidence for supplementation with vitamin D for general health, and improving all-cause mortality isn't there. That's why I wrote:
>Ideally that could be done with sunlight, or food high in vitamin D - for example oily fish, liver, dried-shitake, ...
But there's a sharp difference between the general health, then general respiratory disease, then COVID-19. As Deva Boone writes:
>But maybe Covid is different. Covid is a respiratory infection, and in meta-analyses severe Vitamin D deficiency does appear to increase the risk of respiratory infections. We also have a plausible mechanism through which Vitamin D could influence Covid. ...
OK, now you quote Deva Boone:
>No, not really. There is suggestive evidence from a small pilot study. There is likely an effect,
Her position is disputed here [0] in the HN comments by kovach
devaboone
>Here is what the article states: "Therefore, a multivariate logistic regression analysis was performed to adjust the model by possible confounding variables such as hypertension and type 2 diabetes mellitus for the probability of the admission to the Intensive Care Unit in patients with Calcifediol treatment vs Without Calcifediol treatment (odds ratio: 0.03 (95%CI: 0.003-0.25) (Table 3). The dependent variable considered was the need to be treated or not in ICU (dichotomous variable).) CI:-0.30 - 0.03 p:0.08." The statement is worded in a confusing way, but that is a non-significant p value. Of course we should not put too much into "statistical significance" but it is interesting to note.
kovach
>The only reason that p value is a bit high in that second multivariate analysis is because of the uncertainty of how much all the different risk factors like hypertension, T2DM, age >= 60 etc. affect ICU admission numbers.
But even with those variables controlled, the 95% confidence interval is 0.003-0.25, which at worst is a 4-fold reduction in ICU risk.
>
>We should also note that the Calcifediol treatment group had 14 patients ≥ 60 years old, and the non-Calcifediol group had 5. So the study looks even better with that in mind...
Another thing about this study, is that it's actually megadosing. IIRC, something like 100,000 IU on day 1, 50,000 IU on day 3.
That's probably safe in the short-term in a hospital setting as devaboone states. But further more, it's probably necessary in the context of keeping COVID-19 patients out of the ICU. If they have COVID-19 because they're low in vitamin-D, then a 5000 IU capsule is probably not going to be enough.
That's why I'm advocating to mass-test the at-risk population, and supplement until they're above 30 ng/ml.
First of all I'd like to preface this by saying that everything I write is with a light heart, and I'm not actually 'angry' or feeling any sort of ill will towards you. I know everything is weird now with COVID, and sometimes when we say stuff on the internet it might sound more aggressive than it is intended to. So, no matter what our different opinions are I love you dude, and if we were in person I'd buy you a beer.
That being said.
What do you think causes rickets? Where does Vitamin D come from? What used to cause outbreaks of rickets?
It is a completely plausible proxy for an unhealthy lifestyle. As in, not well or on the road to being not well (not judging those folks, but they're unhealthy and we want to help them get better because they're fellow humans and we love them).
So, I don't know, in summary, Vit D is complicated. That's all.
