Misleading assertions unjustied assumptions and additional limitations of a study by Patone et al. described in the article Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age

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Misleading assertions, unjustiﬁed assumptions, and additional limitations of

a study by Patone et al., described in the article “Risk of Myocarditis After

Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age

and Sex”

Paul Bourdon1, PhD; Spiro Pantazatos2, PhD

Abstract: We describe several shortcomings of a study by Patone et al., whose ﬁndings were recently published

in the American Heart Association Journal Circulation, including the following:

•The study’s principal conclusion, as initially stated, is “Overall, the risk of myocarditis is greater after SARS-

CoV-2 infection than after COVID-19 vaccination and remains modest after sequential doses including a

booster dose of BNT162b2 mRNA vaccine.” However, Patone et al. never attempt to assess the incidence

of myocarditis in their study population following SARS-CoV-2 infection. Rather, they make an untenable

assumption that all infections occurring in their study population are associated with (reported) positive

COVID-19 tests. Using publicly available data from the UK’s ONS and NHS, we show that Patone et al.’s

estimates, for the unvaccinated, of myocarditis incidence associated with infection are likely overestimated

by a factor of at least 1.58. When this factor is taken into account, in, e.g., the incidence rate ratios (IRRs)

of the authors’ Table 3, we ﬁnd that, for men under age 40, the risk of myocarditis after dose 2 of Pﬁzer’s

BNT162b2 is higher than post-infection risk in the unvaccinated (while Table 3 suggests the opposite is

true).

•The method Patone et al. use to compute the incidence of myocarditis among the unvaccinated after a

positive COVID test may overestimate risk. The authors assume, without justiﬁcation, that unvaccinated

persons hospitalized during the study period with positive-test-associated myocarditis would later choose to

vaccinate (and thereby enter the study population already having experienced the event of interest) with

the same probability as unvaccinated persons who have had a positive SARS-CoV-2 test. We present a

plausibility argument that suggests a possible further exaggeration of myocarditis hospitalization risk post

infection by a factor of 1.5.

•Patone et al. fail to discuss important limitations of their study with respect to guiding public health rec-

ommendations. For instance, the study period is 1 December 2020 until 15 December 2021. An insigniﬁcant

number of cases contributing to the study’s ﬁndings were Omicron-variant cases. Thus, the study’s estimates

of myocarditis risk following infection do not speak to the risk following Omicron infection, which is recog-

nized to be milder than that of previous variants. In fact, a study by Lewnard et al. suggests hazard ratios

for severe clinical outcomes are reduced across the board for Omicron versus Delta, with hazard reduction

“starkest among individuals not previously vaccinated against COVID-19”; e.g., the adjusted hazard ratio

for mortality is 0.14 (0.07, 0.28) for the unvaccinated. Thus, relative to Omicron, we expect that myocarditis

incidence rates following infection will be lower than even the appropriately corrected rates (see the preceding

two bullet points) based on Patone et al.’s data.

1. Introduction

On 22 August 2022, a research article [1], titled “Risk of Myocarditis After Sequential Doses of COVID-

19 Vaccine and SARS-CoV-2 Infection by Age and Sex” by Patone et al. was published in the American

Heart Association Journal Circulation. The article reports on a case-series study, stratiﬁed by age and sex,

designed to evaluate the association between COVID-19 vaccination and myocarditis as well as between

COVID-19 infection and myocarditis. For Patone et al.’s study, a case of myocarditis is one that results in

death or in hospital admission for myocarditis—some of these admissions occurred in temporal proximity

(1 to 28 days) to a COVID-19 vaccination, some in temporal proximity to a positive COVID test, and

some, “baseline cases,” did not have either of these temporal associations.

Patone et al.’s study population consists of 42,842,345 residents of England, ages 13 and up, receiving

at least one dose of a COVID-19 vaccine during the study period 1 December 2020 until 15 December

2021. Over the course of the study period, 5,934,153 (13.9%) of the study population tested positive for

SARS-CoV-2, including 2,958,026 (49.8%) before their ﬁrst vaccination.

1Professor of Mathematics, General Faculty, at the University of Virginia (Retired); Formerly, Cincinnati Professor of

Mathematics at Washington & Lee University

2Assistant Professor of Clinical Neurobiology at Columbia University Irving Medical Center; Molecular Imaging and Neu-

ropathology Division, New York State Psychiatric Institute, New York, NY

2010 Mathematics Subject Classiﬁcation: Primary 92C50; Secondary 37M99

arXiv:2210.14955v3 [q-bio.QM] 23 Mar 2023

2. Risk of Myocarditis After Infection

The principal conclusion of the Circulation article by Patone et al. is stated on its ﬁrst page as follows:

Overall, the risk of myocarditis is greater after SARS-CoV-2 infection than after COVID-19 vac-

cination and remains modest after sequential doses including a booster dose of BNT162b2 mRNA

vaccine. However, the risk of myocarditis after vaccination is higher in younger men, particularly

after a second dose of the mRNA-1273 vaccine.

On page 2, the authors state their conclusion diﬀerently, replacing “SARS-CoV-2 infection” with “positive

SARS-CoV-2 test”:

It is important that we also demonstrated across the entire vaccinated population in England that the

risk of myocarditis after vaccination was small compared with the risk after a positive SARS-CoV-2

test.

However, the authors overestimate risk of myocarditis following infection. In the section “Exposures”

on page 3, Patone et al. state

The exposure variables were a ﬁrst, second, or booster dose of the ChAdOx1, BNT162b2, or mRNA-

1273 vaccines, and SARS-CoV-2 infection, deﬁned as the ﬁrst SARS-CoV-2– positive test in the study

period.

The authors estimate SARS-CoV-2 infections in the study population using the number of positive SARS-

CoV-2 tests recorded for its members but they do not account for underascertainment bias (i.e. infections

that occur that are not associated with a positive test.) The number of COVID infections in a population

may be 3 to 4 times the number of documented COVID cases among its members; for example, an

“Interactive COVID-19 Event Risk Planning Tool,” developed with support from several U.S. sources

including the Centers for Disease Control (CDC) and the National Science Foundation, defaults to 3×to

obtain an estimated number of infections from number of cases for“global events,” based on data from a

number of countries, including the UK. The CDC estimates that 4×is the appropriate multiplier (95%

CI: 3.4, 4.7), at least for the period February 2020–September 2021 in the U.S.

Also, in assessing the risk of myocarditis after infection, every infection should be counted, including

repeat infections (some of which would be documented by a positive test result). In short, the authors

have deﬁned “SARS-CoV-2 infection” in such a way that their study is guaranteed to exaggerate the

true risk of myocarditis after infection—for every case of myocarditis in an infected member of the study

population, there will be a positive SARS-CoV-2 test (e.g., one administered by the hospital where the

member received treatment for myocarditis); however, for many infections in the study population, there

will not be a corresponding positive test. In assessing the number of infections in unvaccinated persons

who later join the study population through getting an initial dose of a COVID vaccine, we cannot simply

multiply a given number of positive-test results by 3 or 4. The number of unvaccinated who eventually join

the study population starts at 42,842,345 and gradually declines—we must keep track of these declining

numbers as well time-varying rates of infection.

We are not the ﬁrst to notice that Patone et al’s study exaggerates the risk of myocarditis after SARS-

CoV-2 infection. For instance, Dr. Vinay Prasad raised this issue 28 December 2021 (in commenting on

an earlier publication based on study data from the period 1 December 2020 to 24 August 2021):

While the denominator for vaccines is known with precision, the true number of infections is un-

known. Many people don’t seek testing or medical care. So the red bar above [illustrating positive-

test-associated excess myocarditis cases] will be shorter if you used a sero-prevalence (aka the correct)

denominator. The authors needed to ﬁx this.

Unfortunately, the authors (Patone et al.) did not “ﬁx this” in their recent article appearing in Circulation.

Thus, we oﬀer a ﬁx here.

As we noted earlier, 2,958,026 of the study population tested positive for SARS-CoV-2 before their ﬁrst

vaccination; 114 myocarditis cases occurred during the study period in this subset of the population 1–28

days from the test date. Based on this raw data (used in Patone et al’s “Main Analysis”), the incidence of

positive-test-associated myocarditis among study-population members while unvaccinated is

114

2,958,026 ≈38.54 cases per million positive tests per 28 days.3

To obtain myocarditis incidence after a COVID infection, we must increase the denominator in the pre-

ceding quotient so that it reﬂects the number of SARS-CoV-2 infections that occurred in study-population

members while they were unvaccinated.

Using publicly available data [2] from the UK’s Oﬃce of National Statistics estimating cumulative per-

centages of England’s population that would have—assuming universal testing—tested positive for SARS-

CoV-2 through a given date as well as National Health Service data [3] providing the total number of 1st

doses of COVID vaccines administered through a given date, we have computed 4,685,095 as a lower bound

on the number of SARS-CoV-2 infections occurring during the study period in members of the study pop-

ulation while they were unvaccinated. (See the appended supplementary analysis “Estimating the Number

of SARS-CoV-2 Infections in Members of Patone et al.’s Study Population Before Vaccination.”) Thus, an

estimate of the incidence of myocarditis after a COVID infection among study-population members while

unvaccinated is 114

4,685,095 ≈24.33 cases per million infections per 28 days,4

and the preceding is likely to be an overestimate because the method of computing infections, described

in the supplement, produces a lower bound on number of infections based on ONS and NHS data.

To understand the implications of using a more realistic count of SARS-CoV-2 infections occurring

among members of the study population before they received an initial dose of a COVID vaccine, we’ll

assume that the ratio of infections to positive tests, 1.58 ≈4685095/2958026, is similar for the four major

demographic groups considered in the study: Men <40, Women <40, Men ≥40, Women ≥40. Now

consider the data in Patone et al’s Table 3 that express the risk to men under 40 of contracting myocarditis

after COVID vaccination, or a positive SARS-CoV-2 test, in terms of incident-rate ratios (IRRs):

We have modiﬁed Table 3 from Patone et al.’s article, eliminating rows corresponding to other demographic

groups and adjusting the description of table contents with appropriate strikethroughs. In the third column

from the right, the table has 4.35 as the IRR: 4.35 = M/B, where Mis the test-positive-associated

myocarditis incidence among unvaccinated men under 40 who would later join the study population via

vaccination5and Bis the baseline incidence. We have M= 4.35B, and because we are assuming the number

of infections is roughly 1.58 times the number of (ﬁrst) positive tests, the incidence of myocarditis after

infection should be approximately M/1.58 and the corresponding IRR is M/1.58

B=1

1.58

B=1

1.58 4.35 ≈2.75.

Note this IRR falls below that for the second dose of Pﬁzer’s BNT162b2, namely 3.08, as well as a ﬁrst

dose of Moderna’s mRNA-1273.

3Remark: using the IRR of 11.14 from the “Main Analysis” portion of Table 3, third column from the right, we ﬁnd

the corresponding baseline incidence is approximately 38.54/11.14 ≈3.46 cases per million per 28 days; thus, we arrive at

38.54 −3.46 = 35.08 ≈35 excess cases per million per 28 days, the number reported in Patone et al’s Table 4.

4“infection” here means “ﬁrst infection of the study period”

5M= 13/(number of men under 40 in the study population, in millions, testing positive while unvaccinated)

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Misleading assertions unjustied assumptions and additional limitations of a study by Patone et al. described in the article Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age

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