Covid-19 #14 - Are We Done Yet?

[A wilding]

1 hour ago, The Great Unwashed said:

 But because we know so little about the virus, I'm concerned that even being on the heavier side, even though I'm in relatively good shape, puts me at a higher risk. Or is it just the usual negative health issues that are correlated with a high BMI (high BP, high cholesterol, diabetes, etc.) that constitute a higher risk

There is a lot we don't know yet, but that it is just the usual negative health issues is extremely likely.

[rotting sea cow]

As I said earlier in this thread, politicians should be kept away from scientific debates. They do more harm than good (yes, I also blame Al Gore).

Apparently there is now an open letter to The Lancet and to the authors of the study on which the WHO based its decision to take HCQ out the trials. That study is severely flawed.

Quote

 

Concerns regarding the statistical analysis and data integrity

The retrospective, observational study of 96,032 hospitalized COVID-19 patients from six continents reported substantially increased mortality (~30% excess deaths) and occurrence of cardiac arrhythmias associated with the use of the 4-aminoquinoline drugs hydroxychloroquine and chloroquine. These results have had a considerable impact on public health practice and research.

The WHO has paused recruitment to the hydroxychloroquine arm in their SOLIDARITY trial. The UK regulatory body, MHRA, requested the temporary pausing of recruitment into all hydroxychloroquine trials in the UK (treatment and prevention), and France has changed its national recommendation for the use of hydroxychloroquine in COVID-19 treatment and also halted trials.

The subsequent media headlines have caused considerable concern to participants and patients enrolled in randomized controlled trials (RCTs) seeking to characterize the potential benefits and risks of these drugs in the treatment and prevention of COVID-19 infections. There is uniform agreement that well conducted RCTs are needed to inform policies and practices.

This impact has led many researchers around the world to scrutinize in detail the publication in question. This scrutiny has raised both methodological and data integrity concerns. The main concerns are listed as follows:

1. There was inadequate adjustment for known and measured confounders (disease severity, temporal effects, site effects, dose used).

2. The authors have not adhered to standard practices in the machine learning and statistics community. They have not released their code or data. There is no data/code sharing and availability statement in the paper. The Lancet was among the many signatories on the Wellcome statement on data sharing for COVID-19 studies.

3. There was no ethics review.

4. There was no mention of the countries or hospitals that contributed to the data source and no acknowledgments to their contributions. A request to the authors for information on the contributing centres was denied.

5. Data from Australia are not compatible with government reports (too many cases for just five hospitals, more in-hospital deaths than had occurred in the entire country during the study period). Surgisphere (the data company) have since stated this was an error of classification of one hospital from Asia. This indicates the need for further error checking throughout the database.

6. Data from Africa indicate that nearly 25% of all COVID-19 cases and 40% of all deaths in the continent occurred in Surgisphere-associated hospitals which had sophisticated electronic patient data recording, and patient monitoring able to detect and record “nonsustained [at least 6 secs] or sustained ventricular tachycardia or ventricular fibrillation”. Both the numbers of cases and deaths, and the detailed data collection, seem unlikely.

7. Unusually small reported variances in baseline variables, interventions and outcomes between continents (Table S3).

8. Mean daily doses of hydroxychloroquine that are 100 mg higher than FDA recommendations, whereas 66% of the data are from North American hospitals.

9. Implausible ratios of chloroquine to hydroxychloroquine use in some continents.

10. The tight 95% confidence intervals reported for the hazard ratios appear inconsistent with the data. For instance, for the Australian data this would need about double the numbers of recorded deaths as were reported in the paper. The patient data were obtained through electronic health records, supply chain databases, and financial records. The data are held by the US company Surgisphere. In response to a request for the data Professor Mehra replied: “Our data sharing agreements with the various governments, countries and hospitals do not allow us to share data unfortunately.”

Given the enormous importance and influence of these results, we believe it is imperative that:

1. The company Surgisphere provides details on data provenance. At the very minimum, this means sharing the aggregated patient data at the hospital level (for all covariates and outcomes)

2. Independent validation of the analysis is performed by a group convened by the World Health Organization, or at least one other independent and respected institution. This would entail additional analyses (e.g. determining if there is a dose-effect) to assess the validity of the conclusions

3. There is open access to all the data sharing agreements cited above to ensure that, in each jurisdiction, any mined data was legally and ethically collected and patient privacy aspects respected

In the interests of transparency, we also ask The Lancet to make openly available the peer review comments that led to this manuscript to be accepted for publication.

This open letter is signed by clinicians, medical researchers, statisticians, and ethicists from across the world. The full list of signatories and affiliations can be found below.

https://zenodo.org/record/3864691#.XtDali-ZO7g

 

 

 

 

[Guest]

5 minutes ago, rotting sea cow said:

As I said earlier in this thread, politicians should be kept away from scientific debates. They do more harm than good (yes, I also blame Al Gore).

Apparently there is now an open letter to The Lancet and to the authors of the study on which the WHO based its decision to take HCQ out the trials. That study is severely flawed.

https://zenodo.org/record/3864691#.XtDali-ZO7g

 

 

 

 

Can you break that down in English?

ETA: Asking seriously; I'm too dumb to figure it out.

[rotting sea cow]

27 minutes ago, The Great Unwashed said:

Can you break that down in English?

ETA: Asking seriously; I'm too dumb to figure it out.

Well.  My timeline out the top. I'm not an expert either.

1) Hydroxychloroquine (HCQ), an antimalarial drug (which I once took during a tropical trip) was very early found to be apparently helpful in treating COVID-19 patients.

2) Based on these observational studies, the WHO included it in its observational trials.

3) Trump stuck his dirty fingers in the controversy and clouded the waters.

4) Some studies showed that HQC was apparently harmful. The WHO took the HQC out the trials due to concerns about its safety.

5) That letter describes the many of the methodological flaws of a particular influential study published in a leading journal. There are really many, from suspicious statistics, lack of openness about data and code, to conflict of interests. Basically the letter claims that particular study is crap and should have never guided policy.

[Guest]

4 minutes ago, rotting sea cow said:

Well.  My timeline out the top. I'm not an expert either.

1) Hydroxychloroquine (HCQ), an antimalarial drug (which I once took during a tropical trip) was very early found to be apparently helpful in treating COVID-19 patients.

2) Based on these observational studies, the WHO included it in its observational trials.

3) Trump stuck his dirty fingers in the controversy and clouded the waters.

4) Some studies showed that HQC was apparently harmful. The WHO took the HQC out the trials due to concerns about its safety.

5) That letter describe the many of the methodological flaw of a particular influential study published in a leading journal. There are really many, from suspicious statistics, lack of openness about data and code, to conflict of interests. Basically the letter claims that particular study is crap and should have never guided policy.

The original study that Trump touted or the secondary observational study that caused the WHO to pull HCQ?

[williamjm]

26 minutes ago, The Great Unwashed said:

The original study that Trump touted or the secondary observational study that caused the WHO to pull HCQ?

The letter is referring to that observational study about the risks of HCQ.

[Guest]

1 minute ago, williamjm said:

The letter is referring to that observational study about the risks of HCQ.

So Trump gets a mini-vindication then.

[Ran]

It's one study, but a number of studies and real world cases have seen droves of hospitals stop using HCQ because the side-effects were high and benefits very low. All the early studies come from the same French doctor who has been pushing CQ and HCQ, and all of his studies were also quite flawed.

I wouldn't call it a vindication of Trump.

[rotting sea cow]

I don't give a fig if Trumps gets vindicated or not. For all I care he could take a monthly dose and the world will be improved. He is partially guilty we reached this state of affairs in relation to HCQ research (just to keep things focused). He should have never opened his mouth (I know it is nearly impossible).

The issue here is that a flawed study was used to guide global policy and that basically stopped any research. Yes. It wasn't the only people saying there are safety concerns with HCQ. The drug isn't a candy, but that is true with lots of other drugs and treatments being used to fight the disease. Now, we will likely never know whether it was really helpful or harmful, nor at what stage or dosage or combination with other drugs.

It is still being used in developing countries. But not systematic studies is being carried out.

Quote

Chief doctor Nurettin Yiyit - whose art work is on the hospital walls - says it's key to use hydroxychloroquine early. "Other countries are using this drug too late," he says, "especially the United States.

We only use it at the beginning. We have no hesitation about this drug. We believe it's effective because we get the results."On a tour of the hospital, adding and subtracting protective layers as we go, he explains that Turkey's approach is to "get ahead of the virus", by treating early and treating aggressively. They use hydroxychloroquine and other drugs, along with blood plasma and oxygen in high concentrations.

Dr Yiyit is proud of his hospital's mortality rate of under 1%, and of the empty beds in the intensive care unit. They try to keep patients out of here, and off ventilators.

https://www.bbc.com/news/world-europe-52831017

 

[Guest]

1 hour ago, rotting sea cow said:

I don't give a fig if Trumps gets vindicated or not. For all I care he could take a monthly dose and the world will be improved. He is partially guilty we reached this state of affairs in relation to HCQ research (just to keep things focused). He should have never opened his mouth (I know it is nearly impossible).

The issue here is that a flawed study was used to guide global policy and that basically stopped any research. Yes. It wasn't the only people saying there are safety concerns with HCQ. The drug isn't a candy, but that is true with lots of other drugs and treatments being used to fight the disease. Now, we will likely never know whether it was really helpful or harmful, nor at what stage or dosage or combination with other drugs.

It is still being used in developing countries. But not systematic studies is being carried out.

https://www.bbc.com/news/world-europe-52831017

 

This...just seems like nothing but circular reasoning."We think it works because it works" isn't the same as having a rigorous double-blind study.

It's nothing but anecdotal evidence.

[rotting sea cow]

19 minutes ago, The Great Unwashed said:

This...just seems like nothing but circular reasoning."We think it works because it works" isn't the same as having a rigorous double-blind study.

It's nothing but anecdotal evidence.

Exactly. But the studies showing the opposite aren't better. This is my point. We don't know. The more rigorous trials were stopped because a study published in a leading journal showed that HCQ was dangerous. That letter describes the many failings of that study. As result we are back at the beginnings and we need to start over, wasting months (ages in pandemic times) and lives. 

I'm scientist myself and things like that happens all the time. In my field, for example, it is often said that everything that gets published in Nature proves wrong some years down the road.  Normally it doesn't matter, it is science. We would have expected that scientists get subjected to the highest standards amid this emergency. It's clearly not the case.

 

 

[Impmk2]

29 minutes ago, rotting sea cow said:

Exactly. But the studies showing the opposite aren't better. This is my point. We don't know. The more rigorous trials were stopped because a study published in a leading journal showed that HCQ was dangerous. That letter describes the many failings of that study. As result we are back at the beginnings and we need to start over, wasting months (ages in pandemic times) and lives. 

I'm scientist myself and things like that happens all the time. In my field, for example, it is often said that everything that gets published in Nature proves wrong some years down the road.  Normally it doesn't matter, it is science. We would have expected that scientists get subjected to the highest standards amid this emergency. It's clearly not the case.

 

 

I don't think the letter completely blows the study away - from my reading there are 2 main concerns with it: The opacity of their statistical analysis, and the rigor of their data curation. The former is can be corrected by publishing the tools they've used and allowing external review. The latter is more problematic, but it really depends on whether this is a wholesale problem with their dataset or if it's a relatively small subset. We'll see if the authors have a reasonable response. If not there might be a retraction coming.

I suspect all of these problems are a result of a rush to publish in the current climate, both from a being the first and making your career perspective, and from a wanting to get info out from a public health perspective. For example we've been communicating with a group (who I won't name) who are also doing covid wastewater analysis. They wrote their now published paper in a day, which is utterly nuts. There are several problems with it which we're picking up, from basic miswriting of their methods, to some data analysis about the infected population in their cachement which relies on some (imo extremely unrealistic) assumptions.

[williamjm]

5 hours ago, rotting sea cow said:

The issue here is that a flawed study was used to guide global policy and that basically stopped any research. Yes. It wasn't the only people saying there are safety concerns with HCQ. The drug isn't a candy, but that is true with lots of other drugs and treatments being used to fight the disease. Now, we will likely never know whether it was really helpful or harmful, nor at what stage or dosage or combination with other drugs.

It is still being used in developing countries. But not systematic studies is being carried out.

The UK's big clinical trial of drugs is apparently still including HCQ, see https://www.nature.com/articles/d41586-020-01599-9

Quote

Within a day of the Lancet paper’s publication, the UK’s RECOVERY trial, which has enrolled 10,000 patients to test six potential COVID-19 treatments, consulted its safety board. The board analysed the trial’s interim data and found no sign of harm to study participants from hydroxychloroquine. As a result, the trial can continue enrolling.

The article also quotes the lead of the Lancet paper saying that he wasn't calling for clinical trials to be stopped and thought they should continue.

[Raja]

4 hours ago, rotting sea cow said:

 This is my point. We don't know. The more rigorous trials were stopped because a study published in a leading journal showed that HCQ was dangerous.

The NIH Orchid trial,  the Recovery trial in the UK ( as @williamjm states above) and an outpatient trial from Minnesota are all still going to have an HCQ arm - so if HCQ is effective, we'll find it there. Also, the WHO trial has paused HCQ recruitment until the DMSB reviews their current data just to make sure there isn't any harm, if they don't find it, they would resume recruitment into the HCQ arm.

Obviously decisions shouldn't be made on the back of questionable trials ( I need to read the lancet one before commenting on it specifically), but there are enough trials going on right now with HCQ that if there's a benefit, they'll find it.

[Raja]

On 5/29/2020 at 9:55 AM, Kalbear said:

Georgia, Florida and texas are all doing WAY better than people thought they would do with their outbreaks. Suck on that libs!

Also, for some reason georgia, Florida and texas are having a really horrible case of pneumonia deaths. 

 

Fyi, that tweet has been deleted and a correction has been put forward. Data around this isn't great atm. Need to be careful & see the full data when it comes out ( even the corrected data has some issues if you go to foxjust's tweets)

 

[DireWolfSpirit]

Corrected data still shows unexplained/mysterious spikes in the cheating red states.

[Raja]

2 hours ago, DireWolfSpirit said:

Corrected data still shows unexplained/mysterious spikes in the cheating red states.

What we need to see is if the excess deaths in the state are in keeping with the excess deaths caused by COVID 19 ( As the virus can cause Pneumonia and death certs can say covid 19 & pneumonia both)

Need more clarity on the data as I'm sure there is some under reporting but the corrected data is different than what was initially posted.

[Kalbear]

As pointed out elsewhere (and thank you for the update @Raja) what appears to be true is ALL states are undercounting. Its just a data mess that pisses me off to my engineer core. 

[Ran]

Undercounts are understandable when medicine doesn't work this way. It takes time to do post-mortems, get lab test results, sign and file documents, have them go through the proper chain, etc. So long as the undercount is consistent in the short term to give a sense of trendsand it eventually captures the greater part of actual cases, there's not a lot to be concerned about. 

[Zorral]

30 minutes ago, Ran said:

there's not a lot to be concerned about. 

What do you think that means, beyond you, personally, don't give a damn, Scarlett, Darling.