Sunday, June 21, 2020

Big Data Approach to Treatments for COVID-19 and Other Diseases.

Copyright 2020 Robert Clark

 I want to suggest one approach to finding effective medications to fight COVID-19 is by reviewing large numbers of patient medical histories looking for medications either missing in those histories or those appearing in high numbers in patients with positive outcomes:

Big Data to fight COVID-19 and Other Diseases.

 This searches for effective medications in the reverse sense, by finding medications absent from patients medical histories suggesting they may be protective against the disease.


Big Data to fight COVID-19 and Other Diseases, Page 2.

 This searches for effective medications in the direct sense by finding medications that patients with positive outcomes have in common.

 Studies with thousands of cases to review make this possible. Ideally, you would want to review the medical histories of all the patients with the disease in the country, which can count in hundreds of thousands to millions. In this way you could look at variations in dosages for example, or different combinations of those medications, or variations in the differing risk factors or differing levels of severity of the disease to see which medications are effective in those smaller subcategories in statistically significant numbers.

 But even studies reviewing a few thousands of cases can be useful. For example in the second article above I discussed a Chineses study looking at 6,000 cases that was able to determine a common heartburn medication resulted in a statistically significant increase in survival in severe cases of the disease.

    Bob Clark

Tuesday, June 16, 2020

About the article, “Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19”. UPDATED, 6/26/2020

Copyright 2020 Robert Clark

 Attached below is an email message to the authors of a recent report on hydroxychloroquine and COVID-19, “Observational Study of Hydroxychloroquine in Hospitalized Patients with COVID-19.”  In the first part, I discuss a simplified approach to compensating for the fact that in non-randomized trials you often don't have comparable numbers in the treatment groups compared to the control groups. The method commonly used to compensate for this, "propensity score matching", is computationally complex and often leaves doubt about the validity of the calculations. The method I suggest is simple and can be done by anyone with a hand-calculator.

 In the second part, I discuss a surprising calculation from the data. The authors had concluded that HCQ offered no benefit. But when I calculated the survivability numbers for intubated patients, those on ventilators, I was startled to find the ones on HCQ had twice as good survivability than those not on HCQ! This is an extremely important point because in general the survivability of patients on ventilators is so poor. In fact, in New York only 20% survive being on ventilators with COVID-19. It's mystifying that the authors did not find this significant enough to mention. If you have a medication that can double the chance of survival of patients on ventilators then that fact should be heralded rather than hidden.

 Lastly, the authors have suggested in interviews that their results show HCQ is no better than "standard care". But it was not mentioned that in this study, and in actually in several other studies, what "standard care" means is that the patients are just given other antivirals, and one of them in this study is the potent antiviral and anticancer medication interferon. Just calling the control group under "standard care" would mistakenly give readers the impression that it is perhaps just bed rest and extra oxygen. Then what this study really shows is not that HCQ is ineffective but rather that it is no more effective than those other antivirals. And in actuality, that is also doubtful because those other antivirals did not have the good effect HCQ had for patients on ventilators.

  Robert Clark

UPDATE, 6/26/2020:

 Recent news releases from the RECOVERY trial suggest that hydroxychloroquine offers no added benefit in COVID-19 treatment, but that dexamethasone improves survival 30% for COVID-19 patients on ventilators.

 It is easy to imagine that a drug for various reasons may be more effective for patients with different risk factors. For example, HCQ is an anti inflammatory, as is dexamethasone, so it might be expected to help intubated patients. It is notable that CT imaging can show lung damage due to COVID-19. Then whether or not HCQ does have this effect of reducing lung inflammation for COVID-19 patients might be something observable in real-time on CT scan.

 This would be extremely important for determining its effectiveness in such cases since it could be seen right away if it were working or not, rather than waiting to see if the patient survived or not, which could be due to other factors anyway.

  The reason why the increase in survival with HCQ for ventilated patients wasn’t seen in the overall numbers in that NEJM report was because the ventilated patients were only a small part of the total, approx. 10%, so the ventilated numbers were swamped by the larger numbers of the total cases.

 At least one other study has shown that HCQ improves the survival for ventilated patients:

Research Paper
Published: 15 May 2020
Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19
Bo Yu, Chenze Li, Peng Chen, Ning Zhou, Luyun Wang, Jia Li, Hualiang Jiang & Dao-Wen Wang
Science China Life Sciences (2020)
These data demonstrate that addition of HCQ on top of the basic treatments is highly effective in reducing the fatality of critically ill patients of COVID-19 through attenuation of inflammatory cytokine storm. Therefore, HCQ should be prescribed as a part of treatment for critically ill COVID-19 patients, with possible outcome of saving lives. 
hydroxychloroquine, IL-6, mortalities, COVID-19

 Quite notably the authors observed in real time a reduction in the level of IL-6, a key marker for inflammation, during the treatment with HCQ. So from both CT imaging and inflammation marker readings we could tell if HCQ or other anti-inflammatories were having a beneficial effect on patients under severe disease.

 Also, some other anti-inflammatories such as tocilizumab and methylprednisolone have shown benefits for treating patients under severe disease. This gives further support for the idea that HCQ as an anti-inflammatory should have beneficial effects. For this reason, reports that had shown HCQ or other anti-inflammatories ineffective overall on reducing mortality for patients under severe disease should have the data reviewed to see if specifically patients on ventilators showed increased survival on such anti-inflammatories.


About your article on HCQ treatment for COVID-19.

Robert G Clark
Tue 5/19/2020 6:00 PM

Hello. I was very interested to read your article, “Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19”. I have a few questions I hoped you or someone on your team could answer.

I.) Propensity Score Matching.

In reference to your Table 1 (attached), how do the “propensities” go into the calculation of the likelihood of death? For hypertension, when expanding the non-HCQ no. from 38 to 146 for propensity, do you keep the same ratio of deaths to the total in the category?

For example, if originally, the ratio of deaths was, say, 13/38 in the non-HCQ group in the hypertension category, when expanded to 146 cases is the ratio made to be 50/146? That would seem to me to be a reasonable thing to do since the intention is to compensate for a likely higher rate of death in this category, which would unfairly inflate the mortality rate for the HCQ group since so many of them had hypertension.

 Additionally to that I think you should also report the death ratios for each of the categories for which they are known to be high risk factors, such as hypertension. That is, for hypertension and other risk factors compare the death ratios for the HCQ and non-HCQ groups. There may be significant advantages or disadvantages that you may have missed if you only report the overall death ratios.

II.) The conclusion you drew from your study was that HCQ offered no benefit. But I found a key category in your study where the data did not support that conclusion, the patients on ventilators. COVID-19 patients on ventilators in general have poor outcome. In New York only 20% survive it:

 So it would be extremely important to find drugs that would improve that number.

 Adding “deaths” to “intubated” complicates the analysis. So I looked just at intubated.
From your Table S1 in the Supplemental Appendix file (attached), we get:

For HCQ, 154 - 49 = 105 out of 154 survive, 68.2%
For non-HCQ, 26 - 17 = 9 out of 26 survive, 34.6%

So HCQ is twice as good for survival for intubated patients.

The 34.6% non-HCQ number in your study might be higher than the 20% New York number because the sicker patients were on HCQ in your study, leaving the comparatively healthier patients in your count for non-HCQ intubated patients. Likewise this would also deflate the the survival numbers for the HCQ intubated patients.

 So focusing just on this category of intubated patients gives another example where you would want to break the cases up into the various risk factors and compare survival between HCQ and non HCQ groups. Then you could also calculated a more accurate death rate by using the method I described in part I.) above. Getting survival to ca. 70% using HCQ or perhaps higher would be extremely important.

III.) I was also extremely interested to see that all patients, HCQ and non-HCQ, took interferon. Interferon is a potent antiviral and anti cancer medication. There have been multiple studies now showing interferon shows benefit in treating COVID-19. Then the closeness of HCQ and non-HCQ numbers may have been because the interferon improved the outcomes of both groups. In order to assess the usefulness of HCQ, clearly that would be better illuminated if it were compared to a non-medicated control group.

 No doubt for medical ethical reasons though, you didn’t want to leave any patients unmedicated, even the controls. Also, I presume you also wanted to give the HCQ group the interferon since the HCQ was an unproven medication. By the way Dr. Raoult has been criticized in his studies because he didn’t use controls. He says for medical ethics reason he didn’t want to leave patients unmedicated. I think you can see this is the same reason in yours and other studies assessing HCQ they always gave the control groups other medications.

 But this leaves doubt about the conclusion that HCQ offered no benefit. A more accurate description would be the HCQ offered no ADDITIONAL benefit over using just interferon alone. Let me explain this another way. Suppose other medical professionals took literally the conclusion that HCQ offered no benefit. Then they might conclude they didn’t have to give these patients even under severe disease ANY medication. By making clear instead this was in comparison to interferon they would understand there might be other medications such as interferon that could work just as well or better.

  Thank You,

    Robert Clark

Robert Clark
Dept. of Mathematics
Widener University
One University Place
Chester, PA 19013 USA

Monday, June 1, 2020

Clues to hydroxychloroquine effectiveness in cross-country comparisons. 2nd UPDATE: 7/8/2020.

Copyright 2020 Robert Clark

 Perhaps the evidence for HCQ effectiveness is there if we are willing to put together the clues:

Researchers ponder why covid-19 appears deadlier in the U.S. and Europe than in Asia.

 Graphic showing radically reduced death rates in Asian countries:


National Consumption of Antimalarial Drugs and COVID-19 Deaths Dynamics : an Ecological Study.
“COVID-19 (Coronavirus Disease-2019) is an international public health problem with a high rate of severe clinical cases. Several treatments are currently being tested worldwide. This paper focuses on anti-malarial drugs such as chloroquine or hydroxychloroquine, which have been currently reviewed by a systematic study as a good potential candidate and that has been reported as the most used treatment by a recent survey of physicians. We compare the dynamics of COVID-19 death rates in countries using anti-malaria drugs as a treatment from the start of the epidemic versus countries that do not, the day of the 3rd death and the following 10 days. We show that the first group have a much slower dynamic in death rates that the second group.”

 Here’s the key graphic showing radically reduced death rates in those countries using the antimalarials:


WORLD NEWS MARCH 12, 2020 / 9:51 AM
South Korea experts recommend anti-HIV, anti-malaria drugs for COVID-19
“The groups advised discretion among medical professionals, while recommending the administration of Kaletra, an anti-HIV medication that includes the drugs lopinavir and ritonavir.
Kaletra blocks the ability of HIV to replicate itself, and also inhibits the growth of cancer cells.
South Korean experts are also recommending the use of hydroxychloroquine in combination with the anti-HIV medication. HCQ is sold under the brand name Plaquenil, among others, and is used for the prevention and treatment of malaria.”

Treatment Response to Hydroxychloroquine, Lopinavir/Ritonavir, and Antibiotics for Moderate COVID 19: A First Report on the Pharmacological Outcomes from South Korea.   
“Conclusion: This first report on pharmacological management of COVID 19 from South Korea revealed that HQ with antibiotics was associated with better clinical outcomes in terms of viral clearance, hospital stay, and cough symptom resolution compared to Lop/R with antibiotics or conservative treatment. The effect of Lop/R with antibiotics was not superior to conservative management. The adjunct use of the antibiotics may provide additional benefit in COVID 19 management but warrants further evaluation.”


Indonesia to keep prescribing two malaria drugs for COVID-19 despite bans in Europe.  
“The world’s fourth-most populous nation has since late March recommended that chloroquine and its derivative, hydroxychloroquine, be widely administered, including to coronavirus patients with moderate to severe symptoms, according to Food and Drug Monitoring Agency guidelines.”


India Promotes Hydroxychloroquine, as WHO Stops Trials Over Safety Issues


Commentary on “Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open label non-randomized clinical trial” by Gautret et al.
Mondher Toumi & Samuel Aballea
Journal of Market Access & Health Policy, 8:1, 1758390, DOI:10.1080/20016689.2020.1758390
“Hydroxychloroquine treatment with massive testing and limited confinement has successfully worked in South Korea to control the outbreak with an impress- ively low rate of fatalities[44].”
“So far, European decision-makers have shown very little ability to learn from China [45] and South Korea [44], the only two countries that have been able to control the outbreak. Cultural differences, language barriers, and arrogance from the old Europe may cer- tainly explain why best practice knowledge sharing failed in this situation.”


The Battle Over the Numbers: Turkey’s Low Case Fatality Rate.
BLOG - 4 MAY 2020
“Despite the prevalence of the virus among the population and rapidly increasing infection rates, what is striking is Turkey’s lower death rate. Turkey’s death rate per 1 million population is 37, making it even more successful than most comparable European countries for COVID-19. On the basis of official figures, Turkey ranked better than Germany, which has received a great deal of attention and admiration for its low fatality rates.”
COVID-19 Rates (as of 30 April 2020)
Total cases
Total Deaths
Deaths/1 M population
Tests/1 Million population

Coronavirus: How Turkey took control of Covid-19 emergency.

  • 29 May 2020
Turkey embraces hydroxychloroquine
The country has public health lessons to offer, according to acting head of the World Health Organization (WHO) in Turkey, Dr Irshad Shaikh.
"Initially we were worried," he told the BBC. "They were having 3,500 positive cases per day. But what has worked is testing. And they did not have to wait five or six days for results." He also credits the quarantine, isolation and contract tracing measures but says it's too soon to judge Turkey's treatment protocol for patients.
Controversially that includes the anti-malarial drug, hydroxychloroquine, as standard. It's much touted by President Donald Trump - but has been roundly rejected by the latest international research.
The WHO has temporarily suspended it from their trial of possible treatments for the virus. That followed research published in the Lancet which suggested hydroxychloroquine can cause cardiac problems in Covid-19 patients, and could do more harm than good.
We were given access to a hospital where it has been part of the standard treatment for thousands of patients. The Dr Sehit Ilhan Varank hospital, a two-year old-state hospital, is also state of the art. It's a bright, spacious battlefront against the virus.
Turkey has been using the drug hydroxychloroquine to treat Covid-19 patients

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."

  Bob Clark

UPDATED, 6/10/2020:

 It can be argued that because of confounding effects this is not a firm argument for the effectiveness of HCQ against COVID-19. For example many of the Asian countries have much reduced rates of obesity compared to Western countries, and obesity is a key risk factor for poor outcome for COVID-19.

 More persuasive would be rates of infection and death within the same country. In this post I discussed some doctors in Italy who found HCQ effective with early treatment: Success in Italy reported in early treatment of COVID-19 using hydroxychloroquine.

 Dr. Pietro Garavalli in Italy also found it effective for early treatment:

NEWS | april 28, 2020, 5:40 pm
Hydroxychloroquine VS Covid-19, a therapy considered effective but controversial. The opinion of the Infectivologist Pietro Garavelli.

 And this report noted greatly reduced recent COVID-19 death rates in two Italian provinces and suggests antivirals such as HCQ as a possible explanation:

SARS-CoV-2 lethality decreased over time in two Italian Provinces.

Maria Elena Flacco, Cecilia Acuti Martellucci, Francesca Bravi, Giustino Parruti, Alfonso Mascitelli, Lorenzo Mantovani,  View ORCID Profile Lamberto Manzoli

 "In the two provinces under investigation, the treatment is currently based upon antiviral agents (Chloroquine / Hydroxychloroquine or Lopinavir / Ritonavir), intensive respiratory support [18, 19], and, from the latest days of March, low molecular weight heparin and monoclonal antibodies against inflammatory cytokines (e.g. Tocilizumab), which showed some preliminary, promising results [18, 20-23]."

 In regard to this report however, I am dismayed that the authors decided to release a second version where they deleted all mention of HCQ:

SARS-CoV-2 lethality decreased over time in two Italian Provinces.

Maria Elena Flacco, Cecilia Acuti Martellucci, Francesca Bravi, Giustino Parruti, Alfonso Mascitelli, Lorenzo Mantovani,  View ORCID ProfileLamberto Manzoli
"In the two provinces under investigation, the treatment is currently based upon antiviral agents (lopinavir / ritonavir), intensive respiratory support [18, 19], and, from the latest days of March, low molecular weight heparin and monoclonal antibodies against inflammatory cytokines (e.g. tocilizumab), which showed some preliminary, promising results [18, 20-23]."

 In the first version, the authors report on the antivirals used in treatments which included HCQ. So that must have still been true in the second version released three days later.

  Another case where great differences in COVID-19 death rates occur within the same country is in France:

A Look at COVID Mortality in Paris, Marseille, New York and Montreal.

Posted on May 23, 2020
"COVID mortality is found to be 5 times higher in Paris than in Marseille: 751 deaths per million in Paris, versus 147 deaths per million in Marseille.

The table compiled by France Soir shows that, in Marseille, 3295 COVID patients were treated with the hydroxychloroquine – azithromycin bi-therapy, while 1564 were not.

In Marseille, the case fatality rate among those treated with the bi-therapy was 0.52%, while it was 8.63% for those who did not receive it.

The average case fatality rate was 3.13% for Marseille as whole. In Paris, the case fatality rate reached a staggering 19.12%."

 The 5 times lower mortality in Marseille compared to Paris is quite significant. But even beyond that focusing on Dr. Raoults hospital at IHU Marseille, it has nearly 40 times lower mortality than Paris(!)

 Dr. Raoult in noting this disparity has asserted that COVID-19 is disappearing in Marseille:

Covid-19 is disappearing in Marseille, says leading virologist Dr Raoult.

Issued on: 16/04/2020 - 08:37
Modified: 16/04/2020 - 08:37

  Robert Clark

UPDATED, 7/8/2020:

During a discussion of treatments of COVID-19 the question of Indonesia and Singapore came up. A commonly given explanation for why the Asian countries have death rates at 50 to 100 times lower rates than Western countries is because of their greater testing. However, Indonesia belies that explanation as it counts among the worst in testing but among the best in lowering the death rate:

Indonesia ranks among world's worst in coronavirus testing rate.
Wahyudi Soeriaatmadja
The Straits Times/Asia News Network
Jakarta, Indonesia   /   Tue, April 7, 2020   /   11:11 am

 But as shown in the first image above it counts among the lowest in COVID-19 death rates. And like most of the Asian countries it advocates for extensive use of HCQ:

Indonesia, major advocate of hydroxychloroquine, told by WHO to stop using it.
Kate Lamb and Tom Allard
Indonesia, the world's fourth most populous nation, had told doctors to use the drugs to treat all COVID-19 patients with symptoms from mild to severe. The country has ramped up production since March, granting two dozen licenses to local manufacturers who have churned out millions of doses. 

 Singapore, again like most Asian countries has a remarkably low COVID-19 death rate. Singapore though does not promote HCQ as the primary treatment regimen for COVID-19. But actually it promotes a drug that might be even better, interferon. 

 In this blog post I wrote about an early report that claimed that HCQ was ineffective against COVID-19, "A new possible treatment for COVID-19: interferon alpha." I was really quite amazed in reading the various news articles about the report that the most important take away was missed: the report showed that for the patients in their study interferon alpha had a 100% cure rate against COVID-19! 

 It was really quite remarkable in reading the news articles about the report that the focus was so much on highlighting the (inaccurate) claim that it disproved HCQ, that science journalists and doctors reviewing the results of the report completely missed the surprising results on interferon it contained.

 Since that report numerous other reports have come out reporting on the effectiveness of interferon of various types on treating COVID-19. 

 The Singapore treatment protocol is discussed here:

Interim Treatment Guidelines for COVID-19.
(Version 1.0, dated 2 April 2020). 

 It's interesting also how the Singaporeans breakdown their treatment guidelines. The guidelines recommend Lopinavir-Ritonavir (Kaletra), an antiviral HIV medication, for early treatment, i.e., less than 12 days after symptoms appear, and interferon for later treatment, after 12 days after symptoms appear. 

 Lopinavir-Ritonavir has not been found effective for patients under severe disease, but as an antiviral it would be expected to be most effective for early treatment. And the Singapore guideline document does give a reference to a report, ref. #3, where it was effective for early treatment.

 The fact that antivirals are most effective when given early is a well known fact among infectious disease experts - for other infectious diseases. But, oddly, this doesn't seem to be appreciated for COVID-19. The Singaporean treatment guideline document is rather singular and recognizing this fact in their treatment guidelines on COVID-19.

 Based on the facts that they used an effective antiviral early and included the potent antiviral and anti cancer medication interferon as part of their treatment protocol, and that they have been very successful in keeping their death rates low, I think the Singaporeans treatment strategies should be investigated as possible models to follow for Western countries.

 I must say I have been dismayed that Western countries have been so loathe to consider the treatment strategies used in Asian countries as models for their own treatment strategies. The Western countries have been content to look just at things like the infection tracking policies used, which is certainly important. But with death rates from 50 to 100 times lower than in Western countries it is really unfortunate that the Asian countries treatment strategies are not also considered.

 Another recent study reported on some surprising results:

Evidence That Quinine Exhibits Antiviral Activity against SARS-CoV-2 Infection In Vitro. 

 Not only did quinine have antiviral capability in vitro against COVID-19 but at 10 times better effectiveness than HCQ or CQ! 

 Interesting! I’ve been puzzling about the low death rate in Germany compared to other European nations:

 I once read someone suggest on Facebook that it was because the amount of tonic water, which is quinine in water, that the Germans drink. This possibility was discounted by medical professionals because of the low amount of quinine in tonic water:

 For instance, it might take ten times the amount of quinine you would get in a liter of tonic water to have the beneficial effects of hydroxychloroquine or chloroquine. But if this report is true that quinine itself has ten times the antiviral activity that HCQ or CQ has that means the amount in a liter would be in the therapeutic range!

Note also here that in alcoholic spirits the amount allowed is much higher:

 A couple ways this could be tested would be to see if people who drink tonic water or mixed drinks with tonic water on a regular basis have reduced rates of COVID-19. Another test would be to see if regular users have higher levels of quinine or its metabolites in their blood, and if this is high enough to be protective according to this recent research. 

    Robert Clark

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