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The second wave: estimating the hidden asymptomatic prevalence of COVID-19 in Ireland as we plan for imminent immunisation [version 1; peer review: 1 approved]

Since the first case of COVID-19 in Ireland was recorded policy makers have introduced mitigation measures to control the spread of infection. Infection is spread by both known cases and hidden, undetected asymptomatic cases.  Asymptomatic individuals are people who transmit the virus but display no clinical symptoms. Current evidence reveals that this population is a major contributing factor to the spread of the disease. There is little or no knowledge of the scale of the hidden prevalence of all infections both asymptomatic and symptomatic in Ireland. Furthermore, as governments plan for the roll out of imminent immunisation programmes, the need to know the scale of the hidden prevalence and hence knowledge of the level of immunisation required is essential. We describe and analyse the numbers of reported cases of COVID-19 in Ireland from the first case in February 2020 to mid-December 2020. Using the method of back-calculation we provide estimates of the asymptomatic prevalence of cases from June to December 2020. The descriptive analysis highlighted two epidemic waves of known cases in the time period. Wave two from June to December included twice as many cases as wave one and cases were significantly younger. The back-calculation estimates of asymptomatic prevalence during this time period revealed that for every case known there was an additional unknown case and total prevalence in wave two was estimated to be approximately 95,000 as opposed to the reported 48,390 cases. As prevalence in wave two is known to be spreading within and from younger age groups the role of mixing patterns on spread needs to be disseminated to the wider public to adequately inform them how personal modifications in behaviour can contribute to the control of the epidemic. While universally imposed lockdowns and mitigation measures may be essential, personal behavioural mixing choices are powerful protectors. Open Peer Review


Introduction
Coronavirus disease 2019 or COVID-19 is a novel human respiratory disease caused by the SARS-CoV-2 virus and was first identified in 2019 1 . The surveillance of COVID-19 cases in Ireland was integrated into the existing national Computerised Infectious Disease Reporting (CIDR) system when the notification of the disease was made mandatory in February 2020 2 . Since the first case of COVID-19 in Ireland was recorded policy makers have introduced mitigation measures to control the spread of infection 3 . These measures included public health advice to stay and work at home, restrictions on travel, the closure of educational settings, the cancellation of routine hospital procedures and the isolation and contract tracing of cases identified through testing centres 3 . It has been observed that during these periods of increased and subsequent decreased mitigation measures the reported number of positive cases has decreased and increased in line with the implementation and removal of the measures. These increases and decreases are referred to as epidemic waves 4 and their relationship to the mitigation measures have been clearly established and modelled in Ireland 5 .
Infection we know is spread by both known cases and hidden, undetected asymptomatic cases. Asymptomatic individuals in the context of COVID-19 are people who are carriers of the virus but display no clinical symptoms. Current evidence reveals that this population is a major contributing factor to the spread of the disease, while escaping detection by public health surveillance systems 5 . As a result of this lack of detection public health systems can record only the daily incidence of new known cases and there is little or no knowledge of the actual scale of the hidden cumulative prevalence of all infections both asymptomatic and symptomatic. Furthermore, as governments plan for the roll out of imminent national immunisation programmes, the need to know the scale of the hidden prevalence and hence knowledge of the level of immunisation required is essential to produce the so called 'herd immunity' defined as 'the protection of populations from infection which is brought about by the presence of immune individuals' 5,6 .
The aim of this research was to build on previous modelling work and provide an estimate of the hidden and asymptomatic prevalence of COVID-19 in Ireland during the second wave of infection from October to December 2020. Methods while developed nationally are applicable globally. The objectives were to provide a descriptive and comparative analysis of the first and second waves; to use the back-calculation method to provide an estimate of total prevalence of cases during the second wave and an estimate of the ratio of unknown asymptomatic cases to known symptomatic recorded cases and finally to provide recommendations for future research to enable effective immunisation modelling and planning.

Methods
A plot of the five-day moving average of the reported numbers of COVID-19 cases from the first recorded case on the 29 th of February 2020 to the 8 th of December 2020 was prepared. Descriptive statistics illustrating the numbers of known cases, hospitalised cases, intensive care cases and deaths during this period were computed and cumulate cases by age group were derived. The Chi-squared test of association was used to test the independence of the relationship between the number of cases during an epidemic wave and the numbers of cases reported by age group. This statistic was also used to test the relationship between the number of cases during an epidemic wave the number of hospitalised cases by age group.
Following the statistical analysis of the known cases from the Irish reporting system the back-calculation method was implemented to estimate the numbers of asymptomatic and unknown cases. The method of back-calculation also known as back-projection is well documented and implemented internationally for a wide variety of infectious and social epidemics, from HIV/AIDS to bio-terrorism to heroin use [7][8][9][10] . Previous use of the back-calculation model to predict the incidence and prevalence of disease, particularly AIDS, in the United States, the United Kingdom and Ireland is well documented [11][12][13][14] . The method is known as an indirect method and working with observed symptomatic cases and the known incubation period, the model predicts minimum estimates of the hidden numbers of infected cases. The model is given by, Where C T (t) describes the change in the incidence of the treated and known cases over a defined time period, f(s) is the incubation period distribution of the disease and C U (t) is the unknown number of cases at time t we wish to solve for. The prevalence of the unknown cases over the defined time period is then given by,

Results
A plot of the number of daily cases reported to the national system from the 29 th of February to the 8 th December 2020 are provided in Figure 1. From this we can clearly see that Ireland has recorded to date two epidemic waves each with an increasing and decreasing phase.
From the reported data we can see that during wave one and two a total of 74,439 cases were reported and perhaps more importantly we can also see that greater numbers of individuals were infected within wave two. A total of 25,189 cases were reported in wave one and this almost doubled and increased to 49,250 cases being reported in the second wave. A comparison of the reported cases by age distribution across the two waves is provided in Table 1.
A comparison of the distribution of known cases by age between wave one and wave two is provided in Table 2. We can see that there was a significant change in the age distribution of cases between the two time periods. Within wave one those aged over 65 years of age accounted for approximately between one fifth and one quarter of all reported cases while those under the age of 25 years approximately accounted for one tenth of all cases. Within wave two however this situation reversed with those over the age of 65 accounting for approximately one tenth of all cases and those under the age of 25 accounting for one third of all cases.
Clearly the dynamics of spread changed in wave two as societal mitigation measures were relaxed and prevention measures within older person settings were enhanced. Exploring wave two in more detail using the back-calculation method we initially fitted, using simple regression techniques, separate curves C T (t) to all of the known cases of COVID-19 during both the increasing and decreasing phase of wave two. This included cases where the age was unknown. These curves included exponential, logarithmic, quadratic and cubic models. Details of the best fitting curves amongst all curves fitted are provided in Table 3.
The solutions provided by Comiskey, Snel and Banka 18 for the unknown number of cases C U (t) given the best fitting curve C T (t) were then applied and the results are provided in Table 4. From Table 4, we can see that regardless of the exact nature of the Gamma distribution chosen for the incubation period, the model predicts that for each known infectious case reported there exists approximately one unreported asymptomatic infectious case contributing to infection within the population.

Discussion/conclusions
The principal finding from this study illustrates that in Ireland the true prevalence of the scale of the COVID-19 epidemic may be twice that which has been recorded through testing. Results for the period from early June 2020 to early December 2020 suggest that the while the prevalence of known cases was approximately 48,000, the asymptomatic prevalence was estimated to be approximately a further 46,000 cases. Furthermore, a detailed analysis of the known number of cases illustrated that as of early December 2020 Ireland has experienced two COVID-19 epidemic waves. The   Results presented must be interpreted in light of their limitations. Reported numbers presented were not adjusted for potential reporting delays. In addition, results of the back-calculation method were computed solely for an incubation period described by a Gamma distribution and other distributions may be equally as applicable. However, given these limitations the results presented do provide new and additional knowledge on the scale of asymptomatic prevalence within Ireland. Given the estimates of the asymptomatic prevalence during the second wave, and given that known cases are significantly younger than previously, and according to one study directly related to increases in the movement of people 5 there is a clear need to focus on transmission between and more importantly from those in younger age groups. The impact of mixing patterns on the spread of disease from one age group to another is well established and it is known that mixing between age groups carries far greater risk to the spread of disease than mixing within age groups 19 . It is these mixing patterns which need to be addressed while Ireland awaits vaccine role out and avoids a potential third wave of a COVID-19 epidemic. Further research is needed on asymptomatic prevalence within age groups. Additional research illustrating the role of mixing patterns on spread needs to be disseminated to the wider public to adequately inform them how personal modifications in behaviour can contribute to the control of the epidemic. While universally imposed lockdowns and mitigation measures may be essential, personal behavioural mixing choices are powerful protectors.

Data availability
Publicly available data was accessed from Our World in

Yoon Hong Choi
Statistics and Modelling Economics Department, Public Health England, London, UK Authors estimated the hidden asymptomatic prevalence of COVID-19 in Ireland using the known symptomatic cases and the back-calculation method. Their study is very interesting, important, and timely as the outcomes would provide the policy decision making bodies and public with valuable epidemiological information to implement various control measures to reduce the spread of SARS-CoV-2 in Ireland.

I have few comments and questions to authors:
The definition of the hidden prevalence being estimated is not clear. Authors wrote the following statement: Infection we know is spread by both known cases and hidden, undetected asymptomatic cases. It is not clear whether the result of the back-calculation is unknown asymptomatic cases or unknown both symptomatic and asymptomatic cases. Many of symptomatic cases are still not notified to the surveillance due to lack of testing facility availability or self-isolation due to close contacts or only having mild symptoms (no need to use hospital facility).

1.
Justification of applying the back calculation method to COVID-19.
Since the asymptomatic cases do not develop any clinical symptoms, asymptomatic infections would be cleared without developing any symptoms after the incubation period unlike HIV/AIDS. Any comment on this issue would be helpful to justify using this method for the COVID-19 to estimate asymptomatic cases or prevalence.

2.
The detection rate on symptomatic cases by different time periods was very dependent on the testing priority and facility availability of SARS-CoV-2 in Ireland. This testing facility was poorly available during the first wave and the priority testing was given to only limited people such as who are in long-term care facilities and those with multiple major symptoms in Ireland. This prioritisation could force testing results to detect mainly older adults and very limited number in younger population. Authors need to mention about this time-dependent testing prioritisation and age dependency in different 3.
time periods before they suggested that mitigation and prevention measures during the second wave be responsible for the change of the dynamics.
Are there any seroprevalence studies to evaluate the estimations in this manuscript? Those studies showing antibody levels in the population would be an invaluable measure to evaluate the outcomes of this study as the vaccination was not introduced during the second wave.

4.
Authors only present the estimation results during the second wave as the title described.
Could you also show the results in the first wave as well? Or, is there any particular reason if not performed?

5.
The objective authors mentioned at the end of the introduction is to provide recommendations for future research to enable effective immunisation modelling and planning. It would be helpful for readers if authors discuss this matter with their findings.

6.
It would be interesting to see authors' view on the impact of various control measures implemented by the Irish government and human behaviour change in different time periods during this pandemic.

7.
It would be interesting to measure hidden symptomatic infections using the fatal cases. There is unignorable uncertainty around the "known" symptomatic infections during different periods through COVID-19. As the infection fatality rate became more measurable during the second wave, It might be interesting to estimate the overall number of symptomatic cases using this infection fatality rate and average time to death from infection.

Is the work clearly and accurately presented and does it cite the current literature? Yes
Is the study design appropriate and is the work technically sound? Yes

If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility? Partly

Are the conclusions drawn adequately supported by the results? Partly
Competing Interests: The first author, Professor Catherine Comiskey, was my PhD supervisor and we have published two papers together in the past. I have not worked with Professor Comiskey since 2003. I reviewed the manuscript impartially.
Reviewer Expertise: Mathematical modelling in infectious diseases, epidemiology.
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.