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Bayesian hypothesis testing and hierarchical modelling of ivermectin effectiveness in treating Covid-19

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Abstract and Figures

A recent peer reviewed meta-analysis evaluating ivermectin (Bryant et al, 2021) concluded that this antiparasitic drug is a cheap and effective treatment for reducing Covid-19 deaths. These conclusions were in stark contrast to those of a later study (Roman et al, 2021). Although (Roman et al, 2021) applied the same classical statistical approach to meta-analysis, and produced similar results based on a subset of the same randomized controlled trials data used by (Bryant et al), they claimed there was insufficient quality of evidence to support the conclusion Ivermectin was effective. This paper applies a Bayesian approach, to a subset of the same trial data, to test several causal hypotheses linking Covid-19 severity and ivermectin to mortality and produce an alternative analysis to the classical approach. Applying diverse alternative analysis methods which reach the same conclusions should increase overall confidence in the result. We show that there is strong evidence to support a causal link between ivermectin, Covid-19 severity and mortality, and: i) for severe Covid-19 there is a 90.7% probability the risk ratio favours ivermectin; ii) for mild/moderate Covid-19 there is an 84.1% probability the risk ratio favours ivermectin. Also, from the Bayesian meta-analysis for patients with severe Covid-19, the mean probability of death without ivermectin treatment is 22.9%, whilst with the application of ivermectin treatment it is 11.7%. To address concerns expressed about the veracity of some of the studies we evaluate the sensitivity of the conclusions to any single study by removing one study at a time. In the worst case, where (Elgazzar 2020) is removed, the results remain robust, for both severe and mild to moderate Covid-19. The paper also highlights advantages of using Bayesian methods over classical statistical methods for meta-analysis. All studies included in the analysis were prior to data on the delta variant. NOTE: there is an error in the appendix (page 11: binomial formula has p_i instead of x_i in the combinatorial term)
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Bayesian hypothesis testing and hierarchical modelling of
ivermectin effectiveness in treating Covid-19
Martin Neil and Norman Fenton
Risk Information and Management Research
School of Electronic Engineering and Computer Science,
Queen Mary University of London
18 August 2021
Abstract
A recent peer reviewed meta-analysis evaluating ivermectin (Bryant et al, 2021) concluded
that this antiparasitic drug is a cheap and effective treatment for reducing Covid-19 deaths.
These conclusions were in stark contrast to those of a later study (Roman et al, 2021).
Although (Roman et al, 2021) applied the same classical statistical approach to meta-analysis,
and produced similar results based on a subset of the same randomized controlled trials data
used by (Bryant et al), they claimed there was insufficient quality of evidence to support the
conclusion Ivermectin was effective. This paper applies a Bayesian approach, to a subset of
the same trial data, to test several causal hypotheses linking Covid-19 severity and ivermectin
to mortality and produce an alternative analysis to the classical approach. Applying diverse
alternative analysis methods which reach the same conclusions should increase overall
confidence in the result. We show that there is strong evidence to support a causal link
between ivermectin, Covid-19 severity and mortality, and: i) for severe Covid-19 there is a
90.7% probability the risk ratio favours ivermectin; ii) for mild/moderate Covid-19 there is an
84.1% probability the risk ratio favours ivermectin. Also, from the Bayesian meta-analysis for
patients with severe Covid-19, the mean probability of death without ivermectin treatment is
22.9%, whilst with the application of ivermectin treatment it is 11.7%. To address concerns
expressed about the veracity of some of the studies we evaluate the sensitivity of the
conclusions to any single study by removing one study at a time. In the worst case, where
(Elgazzar 2020) is removed, the results remain robust, for both severe and mild to moderate
Covid-19. The paper also highlights advantages of using Bayesian methods over classical
statistical methods for meta-analysis. All studies included in the analysis were prior to data on
the delta variant.
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1. Introduction
Recent studies by (Kory, Meduri, Varon, Iglesias, & Marik, 2021) and (Bryant et al., 2021)
evaluating the evidence on ivermectin were widely welcomed by those who have argued that
this antiparasitic drug is a cheap and effective treatment for Covid-19 infections. The (Bryant
et al., 2021) meta-analysis of randomized controlled trials (RCTs) trials concluded:
“Moderate-certainty evidence finds that large reductions in COVID-19 deaths are
possible using ivermectin. Using ivermectin early in the clinical course may reduce
numbers progressing to severe disease. The apparent safety and low cost suggest
that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic
globally.”
These conclusions contrast with those in (Popp et al., 2021) and, in particular, to those in
(Roman et al., 2021)
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which conducted a similar meta-analysis to (Bryant et al., 2021) using a
subset of the trials. They concluded:
In comparison to SOC or placebo, IVM did not reduce all-cause mortality, length of
stay or viral clearance in RCTs in COVID-19 patients with mostly mild disease. IVM
did not have effect on AEs or SAEs. IVM is not a viable option to treat COVID-19
patients.
A similar, negative conclusion was made earlier by the World Health Organization (WHO)
(WHO (World Health organization), 2021). Despite their own meta-analysis of the 7 best
randomized control trials available at that time showing that ivermectin reduces mortality by
81%, they concluded:
“a recommendation against the use ivermectin in patients with COVID-19 of any
severity, except in the context of a clinical trial”.
The conclusions in (Popp et al., 2021), (WHO (World Health organization), 2021) and (Bryant
et al., 2021) are not, however, based on the results of the statistical analysis of the data,
which were very similar to those of (Bryant et al., 2021) (in fact, statistically, the WHO analysis
provides overwhelming support for the effectiveness of ivermectin with a risk ratio 0.19 and
95% confidence interval (0.09, 0.38)). Instead, as claimed in (Fordham & Lawrie, 2021), these
conclusions are based on a somewhat vague and possibly biased subjective assessment of
the quality of the trials themselves, and erroneously conclude “no effect” from what was merely
weaker evidence of a positive effect. The WHO’s report recommendation on ivermectin is also
inconsistent (based on the evidence presented) with this recommendation in the same report:
“a strong recommendation for systemic corticosteroids in patients with severe and
critical COVID-19
Unlike the previous studies, this paper applies a Bayesian approach (Gelman et al., 2013;
Sutton & Abrams, 2001), to a subset of the same trial data, to test several causal hypotheses
linking Covid-19 severity and ivermectin to mortality. Applying diverse alternative analysis
methods, which reach the same conclusions, should increase overall confidence in the result.
We do not consider the many subjective/medical criteria used to determine the quality of the
studies.
A Bayesian approach also brings with it several advantages over the classical statistical
approaches applied to this trials data thus far. Firstly, it allows the evaluation of competing
1
Note that (Crawford, 2021) has highlighted errors in the data and the analysis carried out by (Roman et al.,
2021)
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causal hypotheses; so here we test whether Covid-19 mortality is independent of Covid-19
severity, treatment or both treatment and severity. Also, given that a causal link can be
established, a Bayesian approach can explicitly evaluate the strength of impact of that causal
link on mortality. These advantages can be obtained within a Bayesian meta-analysis
framework using a hierarchical model which can also take account of ‘zero’ frequency results
which are not estimable in the classical statistical framework. Finally, the Bayesian approach
to confidence intervals leads to the ability to directly interpret confidence intervals in a way
that does not rely on notions of repeated trials, making them easier to understand.
To address recent widely publicised concerns about the veracity of some of the studies
(notably that of (Elgazzar et al., 2020) we also show results from conducting a ‘remove one
study at a time’ sensitivity analysis.
2. Trials Data Used
The trials data
2
analysed in our meta-analysis is summarised in Table 1 and is based on
(Bryant et al., 2021) Figure 4 (which also provides the full references to the individual studies).
In contrast to (Bryant et al., 2021), we have made the following necessary changes:
We have excluded the study by (Niaee et al., 2021) in our analysis because the severe
Covid-19. patients were not separated from the mild/moderate Covid-19 patients in the
trial.
The ivermectin group of the (Lopez-Medina 2021) trial reported zero deaths in 200
patients. However, (Bryant et al., 2021) analysed potential protocol violations and
included in the ivermectin group 75 patients removed by Lopez-Medina 2021 but
included in their supplementary materials
3
. In our analysis we have used zero in 200
patients (as did Roman et al. 2021)
Also note that the ivermectin and control groups of the (Ravkirti et al., 2021) study have 55
and 57 patients respectively not 57 and 58 as stated in (Roman et al., 2021).
2
The full citations reference for the studies are provided in (Bryant et al 2021) and are not repeated here.
3
Lawrie et al private correspondence.
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Table 1: Trial data used in this Bayesian Meta-analysis
3. The Bayesian Meta-analysis
The Bayesian meta-analysis approach has several stages involving learning from data,
determining which causal hypotheses best explain this data, selecting the ‘best’ hypothesis
and then using this to estimate its impact. The stages are linked as follows:
A. Learn the mortality probability distribution from relevant trials for each hypothesis of
concern using a hierarchical Beta-Binomial model.
B. For each causal hypothesis use the model in stage A to learn the mortality probability
distributions relevant to that causal hypothesis.
C. For each causal hypothesis use the learnt probability distributions from stage B to
predict the observed data and calculate the likelihood of observing the data.
D. For all causal hypotheses compute the posterior probability of each hypothesis given
the likelihood of observing the data under that hypothesis and select the most likely
causal hypothesis that explains the data.
E. Estimate the magnitude of impact of the relevant variables, under the selected ‘best’
hypothesis, on mortality.
In the Bayesian approach the data are fixed and the model parameters are unknown and are
estimated from the fixed data. We apply a Beta-Binomial Bayesian learning model for Stage
A in our meta-analysis, a method commonly used in Bayesian statistical learning. For each
trial,, we use a Binomial model to learn the distribution of the mortality probability, , within
that trial from the trial data . Next, we learn the underlying mortality
probability distribution, , which explains the trial probability distributions, and for this
purpose the beta distribution is the natural choice. The Beta distribution has two parameters
α and β which make it sufficiently flexible to accurately model a wide range of (not necessarily
symmetric) distribution shapes. In any Bayesian approach we must provide ‘prior’ probabilities
for all the parameters to be learnt. As specified in the Appendix the parameters are all given
an ignorant prior distribution meaning that any possible value is equally likely. This
Total Deaths Total Deaths
Severe Covid-19 trials
Elgazaar 2020 100 2100 20
Fonseca 2021 52 12 115 25
Gonzalez 2021 36 537 6
Hashim 2020 11 022 6
Okumus 2021 36 630 9
Mild/moderate Covid-19 trials
Ahmed 2020 45 023 0
Babalola 2020 42 020 0
Chaccour 2020 12 012 0
Elgazaar 2020 100 0100 4
Hashim 2020 48 048 0
Lopez-Medina 2021 200 0198 1
Mahmud 2020 183 0180 3
Mohan 2021 100 052 0
Petkov 2021 50 050 0
Ravikirti 2021 55 057 4
Rezai 2020 35 134 0
Total 1105 26 1078 78
Ivermectin
Control
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expresses our ignorance about all mortality probability parameters. It is important to note that
alternative models and priors (such as a model which includes an exponential prior for sample
size) produce very similar results to those reported here. In other words, the analysis is not
sensitive to the particular (reasonable) prior assumptions made.
Model computation uses the computed Binomial likelihoods for the data observed to update
the prior distributions on the Beta to compute posterior distributions for all mortality probability
parameters. Full details and results are given in the Appendix. For further background
information on this type of Bayesian analysis see (Fenton & Neil, 2018).
The four hypotheses being tested (denoted  about the causal connections between
variables deaths (), Covid-19 Severity (), and Treatment (), are as follows:
 death is independent of Covid-19 severity or treatment
 death is dependent on Covid-19 severity only
 death is dependent on treatment only
 death is dependent on Covid-19 severity and treatment
These hypotheses are shown graphically in Figure 1.
Figure 1: Causal hypotheses 
From applying the analysis stages, A to D, the resulting posterior probability of these
hypotheses being true given the data is:

Hence, there is extremely convincing evidence that Covid-19 severity and treatment causally
influence mortality.
To estimate the magnitude of the impact of Covid-19 severity,, and Treatment,, on death,
we need to compute . Figure 2 shows the marginal probability distributions for
mortality for each of the combinations of severity and treatment. While we can still compute
the mean and confidence intervals (CIs) for these distributions (as shown in Table 2), in
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contrast to the classical approach these CIs do not rely on notions of repeated trials. Also, the
classical CIs hide crucial information about where the probability mass is located..
Figure 2: Posterior marginal probability distributions for mortality p from meta-analysis
Mean
95% CI
0.117
(0.019, 0.275)
0.229
(0.125, 0.349)
0.004
(0, 0.0036)
0.0178
0, 0.068)
Table 2: Mean and 95% confidence intervals.
The risk ratio  is the estimated mortality probability of ivermectin patients divided by the
estimated mortality probability of control patients. One of the advantages of the Bayesian
approach is that the shape and scale of the probability distribution for  can be directly
calculated and inspected whilst making minimal statistical assumptions. Figure 3 shows the
marginal probability distribution of . Note that the probability distribution  for
mild/moderate Covid-19 is heavily asymmetric because the lower bounds for  are
zero (see Table 2), hence producing a zero-division computational overflow. For this reason,
classical statistical methods cannot easily estimate this quantity. However, we can instead use
an arithmetically alternative measure that does not suffer from this defect, risk difference,
. The marginal probability distribution for  is also shown in
 
 
 
 
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Figure 3. For mild/moderate Covid-19 there is a clear modal spike around zero, though with
most of the probability mass of this notably skewed distribution lying in the region ,
favouring ivermectin. The centroid of the probability mass is closer to zero difference than for
severe Covid-19, where the centroid is further away from zero. This indicates a stronger effect
of ivermectin treatment on mortality in severe disease than for mild/moderate. It also suggests
our confidence in the evidence for ivermectin treatment for severe Covid-19 is stronger than
for mild/moderate Covid-19, though this is a quantitative question based on the probability
mass for or .
Figure 3: Posterior marginal probability distributions for  and  from meta-analysis
If the  is less than one, then this provides support for the hypothesis that the treatment is
effective (the lower the number the more effective) and if the upper bound of the confidence
interval for the  is less than one then it is conventionally concluded that the treatment is
effective with that level of confidence (95% in this case). In the Bayesian approach, from the
marginal probability distributions shown in Figure 3, we compute the probability that the risk
ratio, , dependent on the severity of Covid-19, as shown in Table 3.
Severe
Mild to Moderate

90.7%
84.1%
Table 3: Probability of risk ratio,  , favouring ivermectin vs control
The  results of the previous studies, together with the  results from our Bayesian
analysis, are shown in Table 4.
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
 95% CI
WHO 2021
0.19
(0.09, 0.38)
Roman et al, 2021 (all mild or moderate cases)
0.37
(0.12, 1.13)
Popp et al, 2021 (all mild or moderate cases)
0.60
(0.14, 2.51)
Bryant et al, 2021 (mild or moderate cases)
0.24
(0.06, 0.94)
Bryant et al, 2021 (severe cases)
0.51
(0.22, 1.14)
Bryant et al, 2021 (all cases)
0.38
(0.19, 0.73)
Bayesian analysis, 2021 (mild or moderate cases)
0.34
(0.00, 26.0)
Bayesian analysis, 2021 (severe cases)
0.48
(0.08, 1.46)
Table 4: Summary of risk ratio results from previous studies and this Bayesian analysis
The  results from our Bayesian analysis are shown in Table 5.

 95% CI
Bayesian analysis, 2021 (mild or moderate cases)
-0.013
(-0.066, 0.020)
Bayesian analysis, 2021 (severe cases)
-0.110
(-0.269, 0.076)
Table 5: Summary of risk difference results from this Bayesian meta-analysis
4. Sensitivity Analysis
We perform a sensitivity analysis to determine the extent to which the results depend on the
trial data from a particular study. We do this by removing one study at a time and reformulating
the model without that data set. The sensitivity analysis on the risk ratio and difference results
are shown in Table 7.
Table 7: Risk ratio and difference summary statistics for each study removed one at a time
P(RD < 0)
Median 95% CI Mean 95% CI P(RR < 1)
Mild to Moderate
Ahmed 2020 0.03 (0,22) -0.014 (-0.06,0.02) 0.84
Babalola 2020 0.03 (0,23) -0.014 (-0.06,0.02) 0.84
Chaccour 2020 0.03 (0,24) -0.014 (-0.07,0.02) 0.84
Elgazzar 2020 0.07 (0,156) -0.009 (-0.06,0.02) 0.78
Hashim 2020 0.03 (0,17) -0.014 (-0.07,0.02) 0.85
Lopez-Medina 2021 0.05 (0,36) -0.015 (-0.07,0.02) 0.83
Mahmud 2020 0.06 (0,135) -0.011 (-0.07,0.02) 0.79
Mohan 2021 0.04 (0,18) -0.015 (-0.07,0.02) 0.85
Petkov 2021 0.03 (0,17) -0.015 (-0.07,0.02) 0.85
Ravikirti 2021 0.06 (0,145) -0.005 (-0.05,0.02) 0.78
Rezai 2020 2.E-04 (0,8) -0.017 (-0.07,0.01) 0.91
All included 0.03 (0,26) -0.013 (-0.07,0.02) 0.84
Severe
Elgazzar 2020 0.72
(0.24,1.73)
-0.07 (-0.23,0.11) 0.77
Fonseca 2021 0.34
(0.05,1.16)
-0.15 (-0.30,0.02) 0.96
Gonzalez 2021 0.41
(0.04,1.43)
-0.13 (-0.29,0.07) 0.92
Hashim 2020 0.63
(0.09,1.75)
-0.09 (-0.26,0.12) 0.86
Okumus 2021 0.43
(0.04,1.54)
-0.11 (-0.27,0.08) 0.90
All included 0.48
(0.08,1.46)
-0.11 (-0.27,0.08) 0.91
Risk Ratio (RR )
Risk Difference (RD )
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For Mild to Moderate Covid-19 the removal of any single study clearly does not substantially
affect the conclusion, with  lying in the range {0.78, 0.91}. For Severe Covid-19 this
range is {0.77, 0.96} suggesting that if the (Fonseca 2021) or (Gonzalez 2021) were removed
from the meta-analysis the support for the effectiveness of the treatment would substantially
improve, and in the case of removing (Fonseca 2021) this would increase confidence, that the
risk difference is below zero, beyond 95%.
We can re-examine the causality hypothesis under the most unfavourable conditions to the
difference hypothesis, which occurs when the (Elgazzar 2020) trial is removed. The posterior
probability distribution for the four hypotheses are:

So, clearly the causality hypothesis test still strongly supports  even in the absence of
(Elgazzar 2020).
5. Conclusions
This Bayesian meta-analysis has shown that the posterior probability for the hypothesis of a
causal link between Covid-19 severity ivermectin and mortality is over 99%. From the
Bayesian meta-analysis estimates the mean probability of death of patients with severe Covid-
19 to be 11.7% (CI 1.9 27.5%) for those given ivermectin compared to 22.9% (CI 12.5
34.9%) for those not given ivermectin. For the severe Covid-19 cases the probability of the
risk ratio being less than one is 90.7% while for mild/moderate cases this probability it is
84.1%.
By removing one study at a time, we were able to evaluate the sensitivity of the conclusions
to a single study. In the worst case, where (Elgazzar 2020) is removed the results remain
robust, for both severe and mild to moderate Covid-19. It should be noted that the composite
study of (Niaee 2021) was already excluded for the reasons given. Also, we can identify those
studies, which, were they not to be included would lead to an increase in the confidence in the
treatment effect.
In our view this Bayesian analysis, based on the statistical study of the RCT data, provides
sufficient confidence that ivermectin is an effective treatment for Covid-19 in reducing
mortality. This belief supports the conclusions of (Bryant et al., 2021) over those of (Roman et
al., 2021). The conclusions of (Roman et al., 2021) are based on the subjective assessment
that the RCTs were ‘low quality’ but even taking this into account simply means weaker
evidence of a positive effect, rather than ‘no effect’. Moreover, it is important to point out that
there are also many observational studies which provide additional evidence of the
effectiveness of ivermectin (CovidAnalysis, 2021; Kory et al., 2021; Santin, Scheim,
McCullough, Yagisawa, & Borody, 2021). Unlike our analysis, which was restricted to effect
on mortality, this includes evidence of the effectiveness of ivermectin in reducing infection or
hospitalizations.
The paper has also highlighted the advantages of using Bayesian methods over classical
statistical methods for meta-analysis, which is especially persuasive in providing a transparent
marginal probability distribution for both risk ratio  and risk difference, . Furthermore, we
show that using  avoids the estimation and computational issues encountered using  ,
thus making full and more efficient use of all evidence, without ad hoc “continuity corrections”
for avoidance of division-by-zero anomalies.
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Data and Models
All of the models and data used in this work are available in a zip file, which can be downloaded
from: http://www.eecs.qmul.ac.uk/~norman/Models/ivermectin_models.zip
The models can all be run using the free trial version of AgenaRisk:
https://www.agenarisk.com/agenarisk-free-trial
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controlled trials. MedRxiv, 2021.05.21.21257595. https://doi.org/10.1101/2021.05.21.21257595
Santin, A. D., Scheim, D. E., McCullough, P. A., Yagisawa, M., & Borody, T. J. (2021). Ivermectin: a
multifaceted drug of Nobel prize-honored distinction with indicated efficacy against a new global
scourge, COVID-19. New Microbes and New Infections, 100924.
https://doi.org/10.1016/J.NMNI.2021.100924
Sutton, A. J., & Abrams, K. R. (2001). Bayesian methods in meta-analysis and evidence synthesis.
Statistical Methods in Medical Research, 10(4), 277303.
WHO (World Health organization). (2021). Therapeutics and COVID-19: Living Guideline. Retrieved
from https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2021.2
11
Appendix
The stages in the analysis are organised as follows:
A. Learn the mortality probability distribution from relevant trials for each hypothesis of
concern using a Beta-Binomial hierarchical model.
B. For each causal hypothesis use the model in stage A to learn the mortality probability
distributions relevant to that causal hypothesis.
C. For each causal hypothesis use the learnt probability distributions from stage B to
predict the observed data and calculate the likelihood of observing that data.
D. For all causal hypotheses compute the posterior probability of each hypothesis given
the likelihood of observing the data under that hypothesis and select the most likely
causal hypothesis that explains the data.
E. Estimate the magnitude of impact of the relevant variables, under that hypothesis, on
mortality.
For each hypothesis and combination of Covid-19 severity and treatment variable state we
learn the corresponding mortality probability distribution using a hierarchical Beta-Binomial
model (where is the number of studies, is the number of patients and is the number of
deaths in study ):
  





where the mortality probability, , is determined by two parameters, and that model the
global distribution of variables across the studies, where each is determined by its local
data . The prior distributions chosen for  induce an ignorant prior with a mean
 with a distribution broadly flat in the range [0, 1]. Note that here the same prior is used for
and thus favouring neither control nor treatment.
An example of the structure of the Bayesian model used in steps A to C is shown in Figure 4,
as a Bayesian Network, where we learn the probability distribution for  
  from the relevant studies using data pairs  for deaths
and number of subjects in given trial.
12
Figure 4: Meta analysis Bayesian Network
Once we have learnt  from the data we need to determine how well the learnt
distribution explains that data under each hypothesis . Note that each hypothesis has
a different number of mortality probability parameters, ,determined by the number of states
for each variable for that hypothesis. So, for  we only have one probability to
determine. For  we have two mortality probabilities to consider, one for severe
Covid-19 and another for mild-moderate Covid-19, and so on.
As the number of mortality probability parameters to be estimated under each hypothesis
increases the smaller the amount of data available to estimate each one. This leads to greater
variance in predictions of the data when there are more parameters and, thus, models with
more parameters are penalised by Occam’s razor.
To test the predictions of the data under each hypothesis, , we use Bayes:

Here we assume the prior probabilities  are uniform and we can calculate 
as:


which is simply the product of likelihoods over all trials data, using the learnt variables for
the given hypothesis. Given the uniform prior assumption the posterior belief in each causal
hypothesis is simply: . The results are shown in Table 5.
13
Table 5: Summary statistics of distributions and resulting likelihood predictions
The above description takes us up to stage D and established the support for each causal
hypothesis. Here there was overwhelming support for hypothesis  and hence we use the
causal structure for this hypothesis to compute the necessary impact statistics at stage E:
- compute the risk ratio ().
- compute the risk difference ().
- determine the probability of the risk ratio being less than one.
The relevant computations here are:





All calculations are carried out using AgenaRisk Bayesian network software (Agena Ltd,
2021). All models used are available on request and all can be run in the free trial version of
AgenaRisk.
Hypothesis
Median
Mean 95% CI Likelihood
Joint
likelihood
Posterior
probability
H1 P(Death) 1.11% 5.78% (0, 35.8) P(Data) 2.97E-28 2.97E-28 0.000
H2
P(Death | C = Severe) 16.52% 17.20% (5.5, 33.13) P(Data | C = Severe) 5.65E-13 1.29E-21 0.009
P(Death | C = Mild/Moderate) 0.31% 0.86% (0, 4.74) P(D ata | C = Mild/Moderate) 2.29E-09
H3
P(Death | T = Ivermectin) 0.04% 3.37% (0, 23.35) P(Data | T = Ivermectin) 4.30E-11 6.86E-28 0.000
P(Death | T = Control) 3.63% 7.62% (0, 37.82) P(Data | T = Control) 1.60E-17
H4
P(Death | S = Severe, T = Ivermectin) 10.74% 11.71% (1.93, 27.62) P(Data | S = Severe, T = Ivermectin) 2.17E-06 1.40E-19 0.991
P(Death | S = Mild/Moderate, T = Ivermectin) 0.03% 0.42% (0, 3.13) P(Data | S = Mild/Moderate, T = Ivermectin) 1.24E-02
P(Death | S = Severe, T = Control) 22.65% 22.91% (12,6, 34.75) P(Data | S = Severe, T = Control) 3.95E-06
P(Death | S = Mild/Moderate, T =Control) 1.20% 1.78% ( 0, 6.89) P(Data | S = Mild/Moderate, T = Control) 1.32E-06
Likelihoo d of Data given p
Summary stat istics for lear nt p distribut ions
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Preprint
Full-text available
Background: We systematically assessed benefits and harms of the use of ivermectin (IVM) in COVID-19 patients. Methods: Published and preprint randomized controlled trials (RCTs) assessing IVM effects on COVID-19 adult patients were searched until March 15, 2021 in five engines. Primary outcomes were all-cause mortality, length of stay (LOS), and adverse events (AE). Secondary outcomes included viral clearance and severe AEs. We evaluated risk of bias (RoB) using the Cochrane RoB 2.0 tool. Inverse variance random effect meta-analyses were performed with quality of evidence (QoE) evaluated using GRADE methodology. Subgroup analyses by severity of disease and RoB, and sensitivity analyses by time of follow-up were conducted. Results: Ten RCTs (n=1173) were included. Controls were standard of care [SOC] in five RCTs and placebo in five RCTs. RCTs sample size ranged from 24 to 398 patients, mean age from 26 to 56 years-old, and severity of COVID-19 disease was mild in 8 RCTs, moderate in one RCT, and mild and moderate in one RCT. IVM did not reduce all-cause mortality vs. controls (RR 1.11, 95%CI 0.16-7.65, very low QoE). IVM did not reduce LOS vs. controls (MD 0.72 days, 95%CI -0.86 to 2.29, very low QoE). AEs, severe AE and viral clearance were similar between IVM and controls (low QoE for these three outcomes). Subgroup analyses by severity of COVID-19 disease or RoB were consistent with main analyses. Sensitivity analyses excluding RCTs with follow up <21 days showed no difference in all-cause mortality but diminished heterogeneity (I2=0%). Conclusions: In comparison to SOC or placebo, IVM did not reduce all-cause mortality, length of stay or viral clearance in RCTs in COVID-19 patients with mostly mild disease. IVM did not have effect on AEs or SAEs. IVM is not a viable option to treat COVID-19 patients.
Article
Full-text available
Background: After COVID-19 emerged on U.S shores, providers began reviewing the emerging basic science, translational, and clinical data to identify potentially effective treatment options. In addition, a multitude of both novel and repurposed therapeutic agents were used empirically and studied within clinical trials. Areas of uncertainty: The majority of trialed agents have failed to provide reproducible, definitive proof of efficacy in reducing the mortality of COVID-19 with the exception of corticosteroids in moderate to severe disease. Recently, evidence has emerged that the oral antiparasitic agent ivermectin exhibits numerous antiviral and anti-inflammatory mechanisms with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups including Unitaid/World Health Organization have undertaken a systematic global effort to contact all active trial investigators to rapidly gather the data needed to grade and perform meta-analyses. Data sources: Data were sourced from published peer-reviewed studies, manuscripts posted to preprint servers, expert meta-analyses, and numerous epidemiological analyses of regions with ivermectin distribution campaigns. Therapeutic advances: A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large "natural experiments" occurred in regions that initiated "ivermectin distribution" campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns. Conclusions: Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.
Article
In 2015, the Nobel Committee for Physiology or Medicine, in its only award for treatments of infectious diseases since six decades prior, honored the discovery of ivermectin (IVM), a multifaceted drug deployed against some of the world’s most devastating tropical diseases. Since March 2020, when IVM was first used against a new global scourge, COVID-19, more than 20 randomized clinical trials (RCTs) have tracked such inpatient and outpatient treatments. Six of seven meta-analyses of IVM treatment RCTs reporting in 2021 found notable reductions in COVID-19 fatalities, with a mean 31% relative risk of mortality vs. controls. The RCT using the highest IVM dose achieved a 92% reduction in mortality vs. controls (400 total subjects, p<0.001). During mass IVM treatments in Peru, excess deaths fell by a mean of 74% over 30 days in its ten states with the most extensive treatments. Reductions in deaths correlated with extent of IVM distributions in all 25 states with p<0.002. Sharp reductions in morbidity using IVM were also observed in two animal models, of SARS-CoV-2 and a related betacoronavirus. The indicated biological mechanism of IVM, competitive binding with SARS-CoV-2 spike protein, is likely non-epitope specific, possibly yielding full efficacy against emerging viral mutant strains.
Background: Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS-CoV-2 infection and COVID-19 treatment is conflicting. Objectives: To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID-19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS-CoV-2 (postexposure prophylaxis). Search methods: We searched the Cochrane COVID-19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without language restrictions to 26 May 2021. Selection criteria: We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARS-CoV-2 infection. Co-interventions had to be the same in both study arms. We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy. Data collection and analysis: We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderate-to-severe COVID-19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVID-19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARS-CoV-2 infection: SARS-CoV-2 infection, development of COVID-19 symptoms, adverse events, mortality, admission to hospital, and quality of life. Main results: We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVID-19 in inpatient settings and four treating mild COVID-19 cases in outpatient settings. One study investigated ivermectin for prevention of SARS-CoV-2 infection. Eight studies had an open-label design, six were double-blind and placebo-controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias. Ivermectin doses and treatment duration varied among included studies. We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of inconsistencies. Ivermectin compared to placebo or standard of care for inpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very low-certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low-certainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very low-certainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low-certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; low-certainty evidence) and duration of hospitalization (mean difference (MD) -0.10 days, 95% CI -2.43 to 2.23; 1 study; 45 participants; low-certainty evidence). No study reported quality of life up to 28 days. Ivermectin compared to placebo or standard of care for outpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low-certainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low-certainty evidence) or non-IMV or high flow oxygen requirement (0 participants required non-IMV or high flow; 1 study, 398 participants; very low-certainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low-certainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low-certainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days. Ivermectin compared to no treatment for prevention of SARS-CoV-2 infection We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very low-certainty evidence). The study reported results for development of COVID-19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARS-CoV-2 infection, hospital admission, and quality of life up to 14 days. Authors' conclusions: Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.
Article
Objective: To evaluate different doses of ivermectin in adult patients with mild COVID-19 and to evaluate the effect of ivermectin on mortality and clinical consequences. Methods: A randomized, double-blind, placebo-controlled, multicenter clinical trial was performed at five hospitals. A total of 180 mild hospitalized patients with COVID-19 confirmed by PCR or chest image tests were enrolled and allocated to six arms including hydroxychloroquine 200 mg twice per day, placebo plus hydroxychloroquine 200 mg twice per day, single dose ivermectin (200 μg/kg), three low interval doses of ivermectin (200, 200, 200 μg/kg), single dose ivermectin (400 μg/kg), and three high interval doses of ivermectin (400, 200, 200 μg/kg). The primary endpoint of this trial was all-cause of mortality or clinical recovery. The radiographic findings, hospitalization and low O2 saturation duration, and hematological variables of blood samples were analyzed. Results: A total of 16.7% (5/30) and 20.0% (6/30) patients died in arms treated with hydroxychloroquine 200 mg twice per day and placebo plus hydroxychloroquine 200 mg twice per day, respectively, and a reduction in mortality rate in patients receiving ivermectin treatment to 0%, 10%, 0% and 3.3% for arms 1-4 were observed. Risk of mortality was also decreased about 15% in the ivermectin treated arms. Conclusions: Ivermectin as an adjunct reduces the rate of mortality, time of low O2 saturation, and duration of hospitalization in adult COVID-19 patients. The improvement of other clinical parameters shows that ivermectin, with a wide margin of safety, had a high therapeutic effect on COVID-19.
Article
Background: Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials. Areas of uncertainty: We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection. Data sources: We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion. Therapeutic advances: Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19-0.73; n = 2438; I2 = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian-Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff-Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%-91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for "need for mechanical ventilation," whereas effect estimates for "improvement" and "deterioration" clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty. Conclusions: Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.
Book
Since the first edition of this book published, Bayesian networks have become even more important for applications in a vast array of fields. This second edition includes new material on influence diagrams, learning from data, value of information, cybersecurity, debunking bad statistics, and much more. Focusing on practical real-world problem-solving and model building, as opposed to algorithms and theory, it explains how to incorporate knowledge with data to develop and use (Bayesian) causal models of risk that provide more powerful insights and better decision making than is possible from purely data-driven solutions. Features • Provides all tools necessary to build and run realistic Bayesian network models • Supplies extensive example models based on real risk assessment problems in a wide range of application domains provided; for example, finance, safety, systems reliability, law, forensics, cybersecurity and more • Introduces all necessary mathematics, probability, and statistics as needed • Establishes the basics of probability, risk, and building and using Bayesian network models, before going into the detailed applications A dedicated website contains exercises and worked solutions for all chapters along with numerous other resources. The AgenaRisk software contains a model library with executable versions of all of the models in the book. Lecture slides are freely available to accredited academic teachers adopting the book on their course.
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This paper reviews the use of Bayesian methods in meta-analysis. Whilst there has been an explosion in the use of meta-analysis over the last few years, driven mainly by the move towards evidence-based healthcare, so too Bayesian methods are being used increasingly within medical statistics. Whilst in many meta-analysis settings the Bayesian models used mirror those previously adopted in a frequentist formulation, there are a number of specific advantages conferred by the Bayesian approach. These include: full allowance for all parameter uncertainty in the model, the ability to include other pertinent information that would otherwise be excluded, and the ability to extend the models to accommodate more complex, but frequently occurring, scenarios. The Bayesian methods discussed are illustrated by means of a meta-analysis examining the evidence relating to electronic fetal heart rate monitoring and perinatal mortality in which evidence is available from a variety of sources.
Ivermectin for COVID-19: real-time meta analysis of 63 studies
  • Covidanalysis
CovidAnalysis. (2021). Ivermectin for COVID-19: real-time meta analysis of 63 studies. Retrieved from https://c19ivermectin.com/