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. 2021 Jul 9;16(7):e0253636. doi: 10.1371/journal.pone.0253636

Regional variation in COVID-19 positive hospitalisation across Scotland during the first wave of the pandemic and its relation to population density: A cross-sectional observation study

Andrew Rideout 1, Calum Murray 2, Chris Isles 3,*
Editor: Karyn Morrissey4
PMCID: PMC8270435  PMID: 34242268

Abstract

Background

There have been large regional differences in COVID-19 virus activity across the UK with many commentators suggesting that these are related to age, ethnicity and social class. There has also been a focus on cases, hospitalisations and deaths rather than on hospitalisation rates expressed per 100,000 population. The purpose of our study was to examine regional variation in COVID-19 positive hospitalisation rates in Scotland during the first wave of the pandemic and the possibility that these might be related to population density.

Methods and findings

This was a repeated point prevalence study. The number of COVID-19 positive patients hospitalised in the eleven Scottish mainland health boards peaked at 1517 on 19th April, then fell to a low of 243 on 16th August before rising slightly to 262 on 15th September. In July, August and September only four boards had more than 5 hospitalised patients. There was a statistically significant relationship between hospitalisation rates and population density on 97.7% of individual days during the first wave of the pandemic (Pearson’s r 0.62–0.93, with 123 of a possible 174 days having p values <0.001). Multiple linear regression analyses performed on data from the 11 mainland boards across six time points suggest that population density accounted for 70.2% of the variation in hospitalisation rate in April, 72.3% in May, 81.2% in June, 91.0% in July, 91.0% in August, and 88.1% in September. Neither population median age nor median social deprivation score at health board level were statistically significant in the final model for hospitalisation.

Conclusion

There were large differences in crude COVID-19 hospitalisation rates across the 11 mainland Scottish health boards, that were significantly related to population density. Given that lockdown was originally introduced to prevent the NHS from being overwhelmed, we believe our results support a regional rather than a national approach to lifting or reimposing more restrictive measures, and that hospitalisation rates should be part of the decision making process.

Introduction

While much has been made of the UK’s COVID-19 death toll, which as of 19th May 2021 was seventeenth highest in the world when expressed per million population [1], less has been written about the determinants of regional variation in coronavirus activity within the UK, or of the local population and social factors required when planning a return towards normal activity in the recovery stage [2]. The possibility that population density might influence virus transmission rates and clinical outcome is of interest given the wide regional variations in COVID-19 positive cases seen throughout the United Kingdom.

Evidence thus far supports an association between population density and virus activity though it is not yet clear from the literature whether density per se is key or whether density is merely a proxy for more important social determinants [38]. It is also evident that the concentration of people within a densely populated area does not necessarily lead to high infection rates if cities adopt robust social distancing, mask wearing and contact tracing measures [9, 10].

Scotland’s population was 5,463,300 in mid-2019 and average population density in Scotland was 70/sq km that year. There are large differences in population density between mainland boards ranging from 10/sq km in Highland, the least densely populated board, to 1072/sq km in Greater Glasgow and Clyde, the most densely populated board [11] (Fig 1). For comparison, average population densities for the rest of the United Kingdom are as follows: England (432/sq km), Wales (152/sq km) and Northern Ireland (137/sq km) [12]. It is against this background that we undertook an analysis of hospitalization of COVID-19 positive patients in Scotland during the first wave of the pandemic. We were particularly interested in the relation between hospitalisation rates, expressed per 100,000 population, and population density.

Fig 1. Map of Scotland showing population densities of the 11 mainland health boards.

Fig 1

Methods

We used Scottish Government data to identify the number of hospitalised COVID-19 positive patients in all eleven Scottish mainland health boards at midnight each night from 26th March to 15th September 2020 [13] and mid 2019 population estimates for Scotland to calculate hospitalisation rates/100,000 population [11]. Our analysis was in three parts. First, we compared crude hospitalisation rates across the 11 Scottish mainland boards. Second we examined the relationship between crude hospitalisation rate (per 100,000 population) and population density (population per km2) for every day (26th March 2020 to 15th September 2020) of the ‘first wave’ of the UK COVID-19 pandemic across the 11 Scottish mainland health boards. Third, we undertook stepwise multiple linear regression analysis with backward elimination in order to determine the effects of age and deprivation on hospital admissions. For descriptive purposes, we selected six time points to illustrate these analyses: 19th April, 15th May, 14th June, 19th July, 16th August and 15th September. 19th April was the peak of the pandemic in Scotland, 14th June was the week hospitalised cases dropped below 5 in five of the 11 Scottish health boards, 16th August was the day of the lowest number of COVID-19 positive hospitalisations in Scotland and 15th September was during the week when the prime minister confirmed that we were beginning to see a second wave of infections [14]. 15th May and 19th July were approximately midway between April-June and June-August time points.

When numbers of COVID-19 positive patients in Scottish hospitals drop below 5 per health board the Scottish Government report these as ‘less than 5’ in order to reduce the risk that patients might be identified. We were able to determine exact numbers of hospitalised patients in Dumfries and Galloway but not the other health boards and opted to allocate a ‘two’ whenever these health boards reported less than five inpatients. We chose not to analyse the number of COVID-19 positive cases in each health board because of the risk of bias due to different testing regimens. Nor did we attempt to compare death rates. This was because some deaths recorded as due to COVID-19 are possible or presumed COVID-19 in patients who have not tested positive for the virus (clinical diagnosis rather than laboratory diagnosis); because not everyone who died with COVID-19 symptoms was tested for the virus, particularly during the early phase of the pandemic; because not everyone who died within 28 days of testing positive for COVID-19 has died of a COVID-19 related illness, and because deaths make up only a small part of total COVID-19 cases, exacerbating small number effects in calculations.

Statistical analyses

We compared crude hospitalisation rates between health boards by chi square test and odds ratios with 95% confidence intervals where appropriate and correlated hospitalisation rates with population density using Pearson’s correlation coefficient. Crude hospitalisation rates, population proportions, confidence intervals, and chi square test were calculated manually, and odds ratios were calculated using Epi Info Statcalc (v7.2.3.1) [15]. Pearson’s correlation coefficients and regression analyses were calculated using JASP Version 0.10.2 [16]. Three covariates were included in the stepwise multiple linear regression analysis: population density, median age, and median deprivation decile (Scottish Index of Multiple Deprivation (SIMD) decile) [17] for each health board. We calculated median SIMD decile for each health board in Scotland as a measure of population experience of deprivation, where SIMD1 represents the 10% of the Scottish population living in greatest deprivation, and SIMD10 the 10% living in the least deprivation. The regression equation was calculated to predict hospitalisation rate based on population density, age and deprivation at all six time points and for all eleven mainland health boards.

Patient and public involvement

No patient or member of the public was involved in the design, analysis or reporting of this study.

Results

Table 1 shows population and population density for each of the 11 mainland health boards together with numbers hospitalised and crude COVID-19 positive hospitalisation rates per 100,000 population on each of the six time points, while Fig 2 shows daily hospitalisation rates for COVID-19 positive patients per 100,000 population in four of these health boards for illustrative purposes: Dumfries and Galloway, a rural health board which has a border with England; Ayrshire and Arran, a neighbouring health board; Highland, the least densely populated mainland health board; and Greater Glasgow & Clyde, the largest and most densely populated board in Scotland. Daily hospitalisation rates for all 11 mainland boards from 26th March to 15th September are available in a S1 File.

Table 1. Population, population density and confirmed COVID-19 hospitalisation rates/100,000 population at six time points during the first wave of the pandemic.

Health Board Population Mid June 2019 (population density/km2) 19th April cases in hospital Hospital-isations/ 100,000 (95% CI) 15th May cases in hospital Hospital-isations/ 100,000 (95% CI) 14th June cases in hospital Hospital-isations/ 100,000 (95% CI) 19th July cases in hospital Hospital-isations/ 100,000 (95% CI) 16th August cases in hospital Hospital-isations/ 100,000 (95% CI) 15th September cases in hospital Hospital- isations/ 100,000 (95% CI)
Ayrshire & Arran 369,360 (110) 91 24.6 (19.6, 29.7) 42 11.4 (7.9, 14.8) 5 1.4 (0.2, 2.5) 2* 0.5 (0.0,1.3) 2* 0.5 (0.0,1.3) 2* 0.5 (0.0,1.3)
Borders 115,510 (24) 43 37.2 (26.1, 48.4) 25 21.6 (13.2, 30.1) 2* 1.7 (0.0,4.1) 2* 1.7 (0.0,4.1) 2* 1.7 (0.0,4.1) 2* 1.7 (0.0,4.1)
Dumfries & Galloway 148,860 (23) 20 13.4 (7.5, 19.3) 2 1.3 (0.0, 3.2) 0 0.00 (0.0, 0.0) 0 0.0 (0.0, 0.0) 1 0.7 (0.0, 2.0) 3 0.8 (0.0, 1.7)
Fife 373,550 (282) 105 28.1 (22.7, 33.5) 75 20.1 (15.5, 24.6) 57 15.3 (11.3, 19.2) 2* 0.5 (0.0, 1.3) 2* 0.5 (0.0, 1.3) 2* 0.5 (0.0, 1.3)
Forth Valley 306,640 (116) 50 16.3 (11.8, 20.8) 21 6.8 (3.9, 9.8) 5 1.6 (0.2, 3.1) 2* 0.7 (0.0, 1.6) 2* 0.7 (0.0, 1.6) 2* 0.7 (0.0, 1.6)
Grampian 585,700 (67) 72 12.3 (9.5, 15.1) 96 16.4 (13.1, 19.7) 56 9.6 (7.1, 12.1) 29 5.0 (3.1, 6.8) 16 2.7 (1.4, 4.1) 20 3.4 (1.9, 4.9)
Greater Glasgow & Clyde 1,183,120 (1072) 593 50.1 (46.1, 54.2) 460 38.9 (35.3, 42.2) 255 21.6 (18.9, 24.2) 171 14.5 (12.3, 16.6) 135 11.4 (9.5, 13.3) 138 11.6 (9.7, 13.6)
Highland 321,700 (10) 45 14.0 (9.9, 18.1) 5 1.6(0.2, 2.9) 7 2.2 (0.6, 3.8) 2* 0.6 (0.0, 1.5) 2* 0.6 (0.0, 1.5) 2* 0.6 (0.0, 1.5)
Lanarkshire 661,900 (295) 180 27.2 (23.2, 31.2) 113 17.1 (14.9, 20.2) 49 7.4 (5.3, 9.5) 19 2.9 (1.6, 4.2) 6 0.9 (0.2, 1.6) 16 2.4 (1.2, 3.6)
Lothian 907,580 (526) 228 25.1 (21.9, 28.4) 200 22.0 (19.0, 25.1) 134 14.8 (12.3, 17.3) 78 8.6 (6.7, 10.5) 81 8.9 (7.0, 10.9) 78 8.6 (6.7, 10.5)
Tayside 417,470 (55) 90 21.6 (17.0, 26.0) 23 5.5 (3.3, 7.8) 6 1.4 (0.3, 2.6) 2* 0.5 (0.0, 1.1) 2* 0.5 (0.0, 1.1) 2* 0.5 (0.0, 1.1)
Scotland 5,463,300 (70) 1520 27.8 (26.4, 29.2) 1066 19.5 (18.3, 20.7) 575 10.5 (9.7, 11.4) 302 5.5 (4.9, 6.2) 243 4.4 (3.9, 5.0) 262 4.8 (4.2, 5.4)

Footnote Table 1: Scottish Government suppressed counts on their website below 5, so a proxy count of 2 cases was used for these dates when true count was not known.

Fig 2. Daily hospitalisation rates for COVID-19 positive patients/100,000 population in Scotland, Ayrshire & Arran, Dumfries and Galloway, Greater Glasgow and Clyde and Highland (shaded).

Fig 2

The number of COVID-19 positive patients hospitalised in the eleven Scottish mainland health boards was 1517 on 19th April, 1062 on 15th May, 575 on 14th June and 302 on 19th July. Numbers fell to a low of 243 on 16th August before rising slightly to 262 on 15th September. Crude hospitalisation rates fell in 10 of 11 health boards between 19th April and 15th May, and between 15th May and 14th June. On 19th July, 16th August and 15th September only four of Scotland’s mainland health boards, namely Greater Glasgow and Clyde, Lothian, Grampian and Lanarkshire, had more than five hospitalised COVID-19 positive patients. Greater Glasgow and Clyde, the health board with the highest population density, had the highest hospitalisation rates throughout the first wave of the pandemic (Fig 2). Significant inter board variations were seen at each of the time points shown in Table 1 (chi square test (df10) p <0.001 on all dates).

Fig 3 shows the relationship between hospitalisation rates and population density on 14th June for illustrative purposes. This relationship was statistically significant on all except four days (26th, 29th and 31st March, and 1st April) during the first wave of the pandemic (Pearson’s correlation coefficient was in the range 0.62–0.93 with 13 p values between 0.05 and 0.01, 34 p values between 0.01 and 0.001, 123 p values <0.001). This was largely driven by increased hospitalisation in Greater Glasgow and Clyde Health Board, which is not only the largest but also the most densely populated Health Board and the Health Board with one of the greater levels of deprivation. When Greater Glasgow and Clyde was removed from the analysis a statistically significant correlation between population density and hospitalisation rates was demonstrated on 115/174 days (66.1% of occasions) during the first wave of the pandemic.

Fig 3. Confirmed COVID-19 hospitalisation rates/100,000 versus population density in all 11 Scottish mainland health boards on 14th June 2020.

Fig 3

Similar graphs showing data for the five other time points are available on request. The graph is shown with a logarithmic axis for clarity.

Multiple linear regression analyses performed on data from the 11 mainland boards across the six time points showed that the independent variables of median age and median deprivation score were not statistically significant in the final model for hospitalisations, confirming that the most significant driver for hospitalisation identified within this study was population density. Significant regression equations were found for 19th April (F(2,8) = 9.409, p = 0.008), with an R2 of 0.702; for 15th May (F(1,9) = 21.980, p = 0.001), with an R2 of 0.709; for 14th June (F(1,9) = 29.01, p < .001), with an R2 of 0.763; for 19th July (F(2,8) = 40.15, p<0.001) with an R2 of 0.909, for 16th August (F(2,8) = 35.63, p<0.001) with an R2 of 0.899, and for 15th September (F(2,8) = 27.57, p<0.001) with an R2 of 0.873. These data suggest that population density accounted for 70.2% of the variation in hospitalisation rate in April, 70.9% in May, 76.3% in June, 90.9% in July, 89.9% in August, and 87.3% in September. The models are not an exact fit (suggesting that there are other factors at play), but provide a reasonable approximation to the observed numbers of hospitalisations in each of the eleven health boards at these six time points.

Data released by the Scottish Government confirm there was sufficient hospital bed capacity across Scotland during the first wave of the pandemic [18].

Discussion

The results of our survey show significant regional variations in hospitalisation rates for COVID-19 positive patients during the first wave of the COVID-19 pandemic in Scotland. These variations were significantly associated with health board population density. The relationship was one of increasing hospitalisation rate being positively associated with greater population density. This was independent of population median age and median social deprivation score at health board level. Hospitalisation peaked 2–3 weeks after lockdown and fell steadily to a low on 16th August. At no point during the first wave of the pandemic was the NHS overwhelmed in Scotland.

Population density could have contributed to the variation in hospitalisation for the following three reasons. First, a low population density may make it easier to practise social distancing. Second, remote and rural areas such as Highland, Borders and Dumfries & Galloway lack the connectivity (namely the large office buildings, socialisation spaces, and multiple modes of public transport) that draws people into close proximity [5]. Third, rural communities have been observed to behave distinctively in times of natural disaster by expressing greater social control, thereby ensuring compliance with lockdown [19]. We acknowledge, however, that population density cannot be the only explanation [9, 10] and recognise the possibility that density may merely be a proxy for other social determinants [46, 8]

If we accept that we are unlikely to abolish risk completely, then we believe it should be possible to relax restrictions earlier in those regions of the UK with lower virus activity when it is judged that the risks of lockdown [20, 21] outweigh risks of the virus, when there is a test, trace and isolate system in place and particularly now that a vaccination programme is well underway. Whilst Reproductive Number (R0) remains the gold standard for measuring the spread of an epidemic, in practice it is based on a number of assumptions and is complex to calculate. An additional measure could be hospitalisation rates within a region, which allow daily small area monitoring of disease spread, albeit with a longer delay caused by the lag between transmission, onset of clinical disease and deterioration to the point of requiring hospitalisation. Other high income countries, including Japan, Germany, South Korea and Hong Kong, have adopted a regional rather than a national approach to lifting or reimposing restrictions based on the number of new cases/100,000 per week [22]. Our data support this approach, which was also the approach taken by the Scottish government during the first wave of the pandemic. Given the extreme pressure on hospital beds during the second wave, we suggest that hospitalisation rates expressed per 100,000 population could be a useful additional metric when deciding whether to lift or reimpose restrictions.

Strengths and limitations

All emergency health care in the UK is free at the point of delivery, allowing equal access for all who require access to medical evaluation and potential hospitalisation. It was never our intention to examine in depth the reasons behind the differences in hospitalisation, nor could we have ever hoped to do so with the dataset to which we had access. We are not trying to infer that hospitalisation rates are purely a function of population density, more that hospitalisation reflects the ability of the NHS to cope with the COVID-19 pandemic. Hospitalisation is likely to be related to other factors such as age, ethnicity, comorbidity, health inequalities and personal behaviours in addition to the characteristics of the circulating virus. At a system wide level, we have shown that population density appears to be a larger driver of need for hospital beds than age and social deprivation, but are unable to determine the relative contributions of ethnicity and comorbidity. We recognise that SIMD identifies deprived areas within Scotland rather than deprived individuals and would anticipate higher burden of infection and hospitalisation in communities with higher levels of socio-economic deprivation. We acknowledge these issues as limitations and suggest they could form the basis for further research.

Conclusions

We have confirmed there were large differences in COVID-19 hospitalisation rates across the 11 mainland Scottish health boards during the first wave of the COVID-19 pandemic. At Health Board level these were significantly related to population density but not to age, social deprivation, or hospital bed capacity, which did not impose an artificial barrier to hospital admission based on clinical need in Scotland during the first wave of the pandemic. Based on these data, and the premise that lockdown was originally introduced to prevent the NHS from being overwhelmed, we believe our results support a regional rather than a national approach to lifting or reimposing more restrictive measures, and that hospitalisation rates should be part of the decision making process.

Supporting information

S1 Checklist

(DOCX)

S1 File

(XLSX)

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Karyn Morrissey

11 May 2021

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Regional variation in COVID-19 positive hospitalisation across Scotland during the first wave of the pandemic and its relation to population density: a cross-sectional observation study.

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Dear Dr. Isles,

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Limitations:

- The conclusion is inappropriate and even dangerous because so many variables were not included in the data analysis such as co-morbidity, PH prevention measures such as quarantine, wearing facial masks and social distancing, lock downs, and spread of COVID through the different health regions during the pandemic.

- Another major issue is that you do not include hospital distribution in these health regions. Hospital distribution and the number of hospital beds or ICU beds or “Covid ward” is a function of population density and therefore this should be checked for multi-collinearity with variance inflation factor (VIF). I would argue the same is true for co-morbidities, age, socio-economic status (not able to work from home) instead of just median age.

- I am also not sure if COVID patients were always hospitalized in their own health region. You mention that briefly but maybe you would be able to quantify that and also how that changed during the pandemic. We had many patients’ transfers in the height of the pandemic to neighboring regional hospitals.

- What about the impact of nursing home or long-term care outbreaks, clearly a population who is at highest risk for hospitalization (and death)?

- The hospitalization rate is inappropriate. You are looking at persons hospitalized and not hospital admissions, correct? Therefore, the percentage of person hospitalized instead of rate should be a better measure.

- I think also time is another important variable to be included. We experienced in Louisiana a first wave of almost close to capacity hospitalizations in New Orleans but then the pandemic moved quickly into more rural parts of the state where it most likely spread through households and worksites or houses of religious worship (based on outbreaks identified)

Minor limitations:

- Cross-sectional study OR is really a prevalence odds ratio (POR)

- Table 1: do not use the term “cases” here since this is confusing, you talk about COVID hospitalizations.

- Reference 14 should be removed. Southwest Louisiana was impacted by two major hurricanes in the midst of the pandemic and experienced a surge in COVID cases, no hospital data available because no hospitals were left. Because of the damage and impact of these 2 storms residents had to evacuate to their extended family or hotels and live in crowded homes so their exposure risk (no social distancing or wearing face masks) increased dramatically plus these evacuees were not inclined to get tested because they had other major issues to deal with..

Reviewer #2: I believe this is an important analysis, and authors have done an admiring job in attempting to address the concerns of Reviewer #1. However, some issues remain:

1-Probably the main deficiency of the present analysis is to treat daily hospitalizations as independent data. However, our knowledge of epidemiology tells us that hospitalizations should track the infections in the community, which is a multiplicative, not additive process. Therefore, the fact that one region has more hospitalization rate than another, **could** simply be due to the size of the initial cluster and subsequent hospitalizations may not provide independent information on this. Indeed, the epidemic curves in Fig. 3 clearly show smooth curves, confirming this possibility. Also, different regions may have epidemics starting at different times, thus comparisons on the same day are not appropriate. One possibility is to look at the total hospitalizations around the peak, say until you reach half the peak height on either side, e.g., in Fig. 3.

2-Two important co-variates that are missing from this analysis are the area of the region, and the level of lockdown (e.g. measured by Google Mobility). It is widely believed that the latter is responsible for stopping the first wave across the world, and thus its level at different regions (e.g. two weeks prior to the peak) is an important co-variate. As to the former, the idea that density is the appropriate quantity to correlate is based on assumption of a uniform 2d distribution. The real population distributions, however, are far from uniform, with larger density near metro areas that slowly falls off into the suburbs and rural areas. Therefore, a notion as lived density or population-weighted density (e.g., https://arxiv.org/abs/2007.00159) would be a more appropriate quantifier of local residential conditions. In lieu of this data, a joint correlation with density, area, and mobility should provide a minimal description of underlying dynamics.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: SUSANNE STRAIF-BOURGEOIS

Reviewer #2: Yes: Niayesh Afshordi

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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Attachment

Submitted filename: PLOSreview_comments to authors.docx

PLoS One. 2021 Jul 9;16(7):e0253636. doi: 10.1371/journal.pone.0253636.r003

Author response to Decision Letter 0


3 Jun 2021

Response to reviewers

Reviewer #1: Limitations:

- The conclusion is inappropriate and even dangerous because so many variables were not included in the data analysis such as co-morbidity, PH prevention measures such as quarantine, wearing facial masks and social distancing, lock downs, and spread of COVID through the different health regions during the pandemic.

We disagree. The fact that we did not include co-morbidity, PH prevention measures such as quarantine, wearing facial masks, social distancing and lock downs, does not alter the fact that there were large differences in COVID-19 hospitalisation rates across the 11 mainland Scottish health boards, and that these were significantly related to population density. The spread of COVID through the different health regions during the pandemic is what we were studying! Given that lockdown was originally introduced to prevent the NHS from being overwhelmed, we believe our results do indeed support a regional rather than a national approach to lifting or reimposing more restrictive measures (this is currently happening in the UK), and that hospitalisation rates should be part of the decision making process (Scotland reports numbers of COVID-19 patients who are in hospital each day by Health Board but it would make much more sense to express these numbers as rates/100,000).

Another major issue is that you do not include hospital distribution in these health regions. Hospital distribution and the number of hospital beds or ICU beds or “Covid ward” is a function of population density and therefore this should be checked for multi-collinearity with variance inflation factor (VIF). I would argue the same is true for co-morbidities, age, socio-economic status (not able to work from home) instead of just median age.

We disagree. Hospital distribution and the number of hospital beds is indeed a function of population density in Scotland where provision is universal, free at point of use (publicly funded) and adequate. Data released by the Scottish Government confirm there was sufficient hospital bed capacity across Scotland during the first wave of the pandemic (Ref 18).

- I am also not sure if COVID patients were always hospitalized in their own health region. You mention that briefly but maybe you would be able to quantify that and also how that changed during the pandemic. We had many patients’ transfers in the height of the pandemic to neighboring regional hospitals.

Not relevant to Scotland. COVID-19 patients were always hospitalized in their own health region. There were no patient transfers to neighbouring regional hospitals during the height of the pandemic

What about the impact of nursing home or long-term care outbreaks, clearly a population who is at highest risk for hospitalization (and death)?

We have reported total hospitalisations for a heterogeneous population which includes nursing home residents. The variable of interest in our study was rurality (population density) not the impact of nursing homes. That would have been a different study.

The hospitalization rate is inappropriate. You are looking at persons hospitalized and not hospital admissions, correct? Therefore, the percentage of person hospitalized instead of rate should be a better measure.

Why is percentage of persons hospitalized a better measure than hospitalisation per 100,000? 300/100,000 is 0.3% after all...

I think also time is another important variable to be included. We experienced in Louisiana a first wave of almost close to capacity hospitalizations in New Orleans but then the pandemic moved quickly into more rural parts of the state where it most likely spread through households and worksites or houses of religious worship (based on outbreaks identified)

We did include time as a variable! Our analysis is of hospitalisation across Scotland during the whole of the first wave of the pandemic.

Minor limitations:

- Cross-sectional study OR is really a prevalence odds ratio (POR)

We now describe the study as a repeated point prevalence study in the methods section

- Table 1: do not use the term “cases” here since this is confusing, you talk about COVID hospitalizations.

Done

- Reference 14 should be removed. Southwest Louisiana was impacted by two major hurricanes in the midst of the pandemic and experienced a surge in COVID cases, no hospital data available because no hospitals were left. Because of the damage and impact of these 2 storms residents had to evacuate to their extended family or hotels and live in crowded homes so their exposure risk (no social distancing or wearing face masks) increased dramatically plus these evacuees were not inclined to get tested because they had other major issues to deal with..

Our reviewer has made some interesting points about what sounds like a very difficult situation in Louisiana. Our paper is, in fact, about rurality in Scotland. We believe the observation that rural communities may behave distinctively in times of natural disaster by expressing greater social control (reference 19) is relevant to our findings.

Reviewer #2: I believe this is an important analysis, and authors have done an admiring job in attempting to address the concerns of Reviewer #1. However, some issues remain:

1-Probably the main deficiency of the present analysis is to treat daily hospitalizations as independent data. However, our knowledge of epidemiology tells us that hospitalizations should track the infections in the community, which is a multiplicative, not additive process. Therefore, the fact that one region has more hospitalization rate than another, **could** simply be due to the size of the initial cluster and subsequent hospitalizations may not provide independent information on this. Indeed, the epidemic curves in Fig. 3 clearly show smooth curves, confirming this possibility. Also, different regions may have epidemics starting at different times, thus comparisons on the same day are not appropriate. One possibility is to look at the total hospitalizations around the peak, say until you reach half the peak height on either side, e.g., in Fig. 3.

We accept all of these points which we feel we have addressed in our discussion when we say ‘An additional measure could be hospitalisation rates within a region, which allow daily small area monitoring of disease spread, albeit with a longer delay caused by the lag between transmission, onset of clinical disease and deterioration to the point of requiring hospitalisation.’ (Discussion, paragraph 3). We go on to argue that ‘other high income countries, including Japan, Germany, South Korea and Hong Kong, have adopted a regional rather than a national approach to lifting or reimposing restrictions based on the number of new cases/100,000 per week.’ The point our paper is attempting to make is that hospitalizations/100,000 could potentially be a more useful metric to consider when making these decisions, given that one of the main purposes of lockdown has been to prevent the health service from being overwhelmed.

2-Two important co-variates that are missing from this analysis are the area of the region, and the level of lockdown (e.g. measured by Google Mobility). It is widely believed that the latter is responsible for stopping the first wave across the world, and thus its level at different regions (e.g. two weeks prior to the peak) is an important co-variate. As to the former, the idea that density is the appropriate quantity to correlate is based on assumption of a uniform 2d distribution. The real population distributions, however, are far from uniform, with larger density near metro areas that slowly falls off into the suburbs and rural areas. Therefore, a notion as lived density or population-weighted density (e.g., https://arxiv.org/abs/2007.00159) would be a more appropriate quantifier of local residential conditions. In lieu of this data, a joint correlation with density, area, and mobility should provide a minimal description of underlying dynamics.

These are undoubtedly important points. It seems highly likely that had we been able to take our analyses to the next level by calculating population weighted density we would have seen an even greater correlation with hospitalisation rates. As it was we found a statistically significant relationship between hospitalisation rates and population density on 97.7% of individual days during the first wave of the pandemic without taking into account the larger population density of inner city areas that slowly falls off into the suburbs and rural areas. To restate the aim of our paper, this is not about the factors that might or might not influence the incidence or prevalence of COVID-19 in different parts of Scotland. We have simply observed that there were huge differences in hospitalisation rates across Scotland during the first wave of the pandemic and shown that these differences were related, at least in part, to population density. Given that lockdown was originally introduced to prevent the NHS from being overwhelmed, we believe our results support a regional rather than a national approach to lifting or reimposing more restrictive measures, and that hospitalisation rates should be part of the decision making process.

________________________________________

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes: SUSANNE STRAIF-BOURGEOIS

Reviewer #2: Yes: Niayesh Afshordi

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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Attachment

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Decision Letter 1

Karyn Morrissey

10 Jun 2021

Regional variation in COVID-19 positive hospitalisation across Scotland during the first wave of the pandemic and its relation to population density: a cross-sectional observation study.

PONE-D-20-38210R1

Dear Prof Isles,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Karyn Morrissey

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thanks for addressing all of my comments even though we still agree to disagree on some issues. :)

I like that your data analysis was done with publicly available PH data! I do hope that this is an ongoing trend so that researchers can utilize more these types of data.

As you stated, the main goal of your manuscript is to look at and decided based on regional and not national data when implementing PH measures during pandemics and epidemics. I think this is a valid and important message which is supported by your manuscript and therefore should be published.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes: SUSANNE STRAIF-BOURGEOIS

Acceptance letter

Karyn Morrissey

30 Jun 2021

PONE-D-20-38210R1

Regional variation in COVID-19 positive hospitalisation across Scotland during the first wave of the pandemic and its relation to population density: a cross-sectional observation study.

Dear Dr. Isles:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Karyn Morrissey

Academic Editor

PLOS ONE

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