The SARS-CoV-2 Alpha variant was associated with increased clinical severity of COVID-19 in Scotland: A genomics-based retrospective cohort analysis

Abstract

Objectives

The SARS-CoV-2 Alpha variant was associated with increased transmission relative to other variants present at the time of its emergence and several studies have shown an association between Alpha variant infection and increased hospitalisation and 28-day mortality. However, none have addressed the impact on maximum severity of illness in the general population classified by the level of respiratory support required, or death. We aimed to do this.

Methods

In this retrospective multi-centre clinical cohort sub-study of the COG-UK consortium, 1475 samples from Scottish hospitalised and community cases collected between 1^st November 2020 and 30^th January 2021 were sequenced. We matched sequence data to clinical outcomes as the Alpha variant became dominant in Scotland and modelled the association between Alpha variant infection and severe disease using a 4-point scale of maximum severity by 28 days: 1. no respiratory support, 2. supplemental oxygen, 3. ventilation and 4. death.

Results

Our cumulative generalised linear mixed model analyses found evidence (cumulative odds ratio: 1.40, 95% CI: 1.02, 1.93) of a positive association between increased clinical severity and lineage (Alpha variant versus pre-Alpha variants).

Conclusions

The Alpha variant was associated with more severe clinical disease in the Scottish population than co-circulating lineages.

Introduction

The Alpha variant of SARS-CoV-2 (Pango lineage B.1.1.7) was first identified in the UK in September 2020 and was subsequently reported in 183 countries [1]. It is defined by 21 genomic mutations or deletions, including 8 characteristic changes within the spike gene (S1 Table) [2]. These are associated with increased ACE-2 receptor binding affinity and innate and adaptive immune evasion [3–6] compared to preceding lineages. The Alpha variant, the first variant of concern (VOC), was estimated to be 50–100% more transmissible than other lineages present at the time of its emergence [7], explaining the transient dominance of this lineage globally.

The presence of a spike gene deletion (Δ69–70) results in spike-gene target failure (SGTF) in real-time reverse transcriptase polymerase chain reaction (RT-PCR) diagnostic assays and provided a useful proxy for the presence of the Alpha variant for epidemiological analysis during this time period [2]. Four large community analyses showed a positive association between the presence of SGTF and 28-day mortality, with hazard ratios of 1.55 (CI 1.39–1.72), 1.64 (CI 1.32–2.04), 1.67 (CI 1.34–2.09) and 1.73 (CI 1.41–2.13) [8–10]. Both SGTF (hazard ratios of 1.52 (CI 1.47–1.57), 1.62 (CI 1.48–1.78)) [11, 12] and confirmed Alpha variant infection (hazard ratios of 1.34 (CI 1.07–1.66) and 1.61 (CI 1.28–2.03) [12, 13] were associated with an increased risk of hospitalisation in community cases, and a smaller study of hospitalised patients found a greater risk of hypoxia at admission in those with confirmed Alpha variant infection [14]. In contrast, other smaller analyses of hospitalised patients found no association between confirmed Alpha variant infection and increased clinical severity based on a variety of indices [15–17]. Limited data are available on the full clinical course of disease with the Alpha variant in relation to co-circulating variants.

Understanding the clinical pattern of disease with new variants of concern is important for several reasons. Firstly, if a variant is more pathogenic than previous variants, this has implications for considering public health restrictions and the optimal functioning of health care systems. Secondly, large numbers of low- and middle-income countries still have less than 50% of their populations having been vaccinated against SARS-CoV-2 [18]. A better understanding of a variant with increased severity is important in modelling the impact of unmitigated infection in these settings. A clear understanding of the behaviour of the Alpha variant, which emerged as a dominant variant in Scotland in the winter of 2020/21, is needed as a baseline to compare the clinical phenotype of variants of concern that have subsequently emerged. Post-Alpha variants, such as Omicron (B.1.1.529), have been shown to be able to evade vaccine-induced immunity and therefore have the potential to spread even in immunised populations [19], so a historical understanding of severity remains important, as it seems unlikely that SARS-CoV-2 infections will be brought under control in the near future.

We aimed to quantify the clinical features and rate of spread of Alpha variant infections in Scotland in a comprehensive national dataset. We used whole genome sequencing data to analyse patient presentations between 1^st November 2020 and 30^th January 2021 as the variant emerged in Scotland and used cumulative generalised additive models to compare 28-day maximum clinical severity for the Alpha variant against co-circulating lineages.

Materials and methods

Sample collection and approvals

We included all Scottish COG-UK pillar 1 samples sequenced at the MRC-University of Glasgow Centre for Virus Research (CVR) and the Royal Infirmary of Edinburgh (RIE) between 1st November 2020 and 30th January 2021. These samples derived from both hospitalised patients (59%) and community testing (41%).

Residual nucleic acid extracts derived from the nose-throat swabs of SARS-CoV-2 positive individuals whose diagnostic samples were submitted to the West of Scotland Specialist Virology Centre and Edinburgh Royal Infirmary Virus laboratory and were sequenced following ethical approvals from the West of Scotland Biorepository (16/WS/0207NHS) and the Lothian Biorepository (10/S1402/33). These samples were sequenced without consent following HTA legislation on consent exemption. Use of Scottish anonymised clinical data linked to virus genomic data without informed consent was granted by the Caldicott guardian for each site and by the Scottish Public Benefit and Privacy Panel (PBPP) for Health and Social Care (2122–0130).

Sequencing and bioinformatics

Sequencing was performed as part of the COG-UK consortium using amplicon-based next generation sequencing [20, 21]. Sequence alignment, lineage assignment and tree generation were performed using the COG-UK data pipeline (https://github.com/COG-UK/datapipe) and phylogenetic pipeline (https://github.com/cov-ert/phylopipe) with pangolin lineage assignment (https://github.com/cov-lineages/pangolin) [22]. Lineage assignments were performed on 18/03/2021 and phylogenetic analysis was performed using the COG-UK tree generated on 25/02/2021. Estimates of growth rates of major lineages in Scotland were calculated from time-resolved phylogenies for lineages B.1.1.7 (Alpha), B.177 and the sub-clades B.177.5, B.177.8, and another minor B.177 sub-clade (W.4). The estimates were carried out utilising sequences from November 2020 –March 2021 in BEAST (Bayesian Evolutionary Analysis by Sampling Trees) with an exponential growth rate population model, strict molecular clock model and TN93 with four gamma rate distribution categories. Each lineage was randomly subsampled to a maximum of 5 sequences per epiweek (resulting in 52 to 103 sequences per subsample, depending on the lineage), and 10 subsamples replicates analysed per lineage in a joint exponential growth rate population model.

Clinical data

Core demographic data (age, sex, partial postcode) were collected via linkage to electronic patient records at the 7 of 14 scottish health boards (covering 78% of the scottish population) for which we had clinical data access approval, and a full retrospective review of case notes was undertaken. Collected data included residence in a care home; occupation in care home or healthcare setting; admission to hospital; date of admission, discharge and/or death and maximum clinical severity at 28 days sample collection date via a 4-point ordinal scale (1. No respiratory support; 2. Supplemental low flow oxygen; 3. Invasive ventilation, non-invasive ventilation or high-flow nasal canula (IV/NIV/HFNO); 4. Death) as previously used in Volz et al 2020 and Thomson et al 2021 [23, 24].

Where available, PCR (Polymerase Chain Reaction) cycle threshold (Ct) and the PCR testing platform were recorded. Nosocomial COVID-19 was defined as a first positive PCR occurring greater than 48 hours following admission to hospital, individuals meeting this criterion were excluded from the study. Discharge status was followed up until 15th April 2021 for the hospital stay analysis. For the co-morbidity sub-analysis, delegated research ethics approval was granted for linkage to National Health Service (NHS) patient data by the Local Privacy and Advisory Committee at NHS Greater Glasgow and Clyde. Cohorts and de-identified linked data were prepared by the West of Scotland Safe Haven at NHS Greater Glasgow and Clyde.

Severity analyses

Four level severity data was analysed using cumulative (per the definition of Bürkner and Vuorre (2019)) generalised additive mixed models (GAMMs) with logit links, specifically, following Volz et al (2020) [23, 25]. We analysed three subsets of the data: 1. the full dataset, 2. the dataset excluding care home patients, and 3. exclusively the hospitalised population. Further details regarding these analyses are provided in S1 Appendix.

Ct analysis

Ct value was compared between Alpha variant and pre-Alpha variant infections for those patients where the TaqPath assay (Applied Biosystems) was used. This platform was used exclusively for this analysis because different platforms output systematically different Ct values, and this was the most frequently used in our dataset (n = 154, Alpha = 38, pre-Alpha = 116). We used a generalised additive model with a Gaussian error structure and identity link, and the same covariates used as in the severity analysis to model the Ct value. The model was fitted using the brms (v. 2.14.4) R package [26]. The presented model had no divergent transitions and effective sample sizes of over 200 for all parameters. The intercept of the model was given a t-distribution (location = 20, scale = 10, df = 3) prior, the fixed effect coefficients were given normal (mean = 0, standard deviation = 5) priors, random effects and spline standard deviations were given exponential (mean = 5) priors.

Hospital length of stay analysis

Hospital length of stay was compared for Alpha variant and pre-Alpha variant patients while controlling for age and sex using a Fine and Gray model competing risks regression using the crr function in the cmprsk (v. 2.2–10) R package [27, 28]. Nosocomial infections were excluded. In total, this analysis had 521 cases (Alpha = 187, pre-Alpha = 334), of which 4 were censored; 352 patients were discharged from hospital and 165 died.

Results

Emergence of the Alpha variant in Scotland

Between 01/11/2020 and 31/01/2021 1863 samples from individuals tested in pillar 1 facilities in Scotland underwent whole genome sequencing for SARS-CoV-2. Of these, 1475 (79%) could be linked to patient records from participating scottish health boards, and were included in the analysis. The contribution of patients infected with the Alpha variant increased over the course of the study, in line with dissemination across the UK during the study period (Fig 1A and 1B). At the time of data collection, two peaks of SARS-CoV-2 infection had occurred in the UK: the first (wave 1) in March 2020 [15] and the second in summer 2020 [29], both in association with hundreds of importations following travel to Central Europe [30]. The second peak incorporated two variant waves (waves 2 and 3), initially of B.1.177 (Fig 1C) and then B.1.1.7/Alpha, radiating from the South of England (Fig 1E). This Alpha variant “takeover” (Fig 1D) corresponded to a five-fold increase in growth rate on an epidemiological scale relative to pre-Alpha lineages (Fig 1F).

[Figure omitted. See PDF.]

A) Waves of SARS-CoV-2 confirmed cases in the UK. B) Seven-day rolling average of daily PCR positive cases (orange) and total number of patients hospitalised (dark blue) with COVID-19 in Scotland during the study period. Grey shaded area represents the period of lockdown beginning 26/12/2020. C) Variants in the UK. D) Proportion of cases by lineage in the clinical severity cohort. E) Variants in Scotland showing three distinct waves in winter and early spring 2020, summer 2020 and autumn/winter, attributed to the shifts from B1 and other variants (light blue) to B.1.177 (dark blue) and then B.1.1.7/Alpha (orange). Waves one and two closely mirror the broader UK situation as they are linked to both continental European and introductions from England. Wave three has a single origin in Kent so Scotland lags England in numbers of cases. F) Estimates of growth rates of major lineages in Scotland from time-resolved phylogenies. Estimates were carried out on a subsample of the named lineages using sequences from Scotland only from November 2020-March 2021 using BEAST and an exponential growth effective population size model.

Demographics of the clinical cohort

The age of the clinical cohort ranged from 0–105 years, (mean 66.8 years) and was slightly lower in the Alpha group (65.6 years vs. 67.2 years). Overall, 59.1% were female; this preponderance occurred in both subgroups and was higher in the Alpha subgroup (60.4% vs 58.6%). In the full cohort, 3.0% were care-home workers and 10.4% were NHS healthcare workers. 5.5% and 5.8% of those infected with the Alpha variant were care-home and other healthcare workers respectively, compared with 2.2% and 12.0% of those infected with pre-Alpha lineages. 12.9% of those in the Alpha subgroup were care-home residents, compared with 21.7% in pre-Alpha. There was also a difference in the proportion of cases admitted to Intensive Care Units: 6.3% of the Alpha group compared with 3.4% for pre-Alpha. Full details of the demographic data of the cohort can be found in Table 1 and full lineage assignments can be found in S2 Table.

[Figure omitted. See PDF.]

Clinical severity analysis

Within the clinical severity cohort there were 364 Alpha cases, 1030 B.1.177 cases, and 81 cases due to one of 19 other pre-Alpha lineages (Fig 2), of which 185 Alpha cases (51%) and 440 pre-Alpha cases (38%) received oxygen or died. Consistent with previous research comparing mortality and hospitalisation in SGTF detected by PCR versus absence of SGTF, we found that Alpha variant viruses were associated with more severe disease on average than those from other lineages circulating during the same time period. In the full dataset, we observed a positive association with severity (posterior median cumulative odds ratio: 1.40, 95% CI: 1.02–1.93). In both the subsets, excluding care-home patients or limiting to hospitalised patients only, the mean estimate of the increase in severity of the Alpha variant was smaller, and the variance in the posterior distribution higher likely due to the smaller sample sizes. Given this uncertainty, we cannot determine whether the association of the Alpha variant with severity in the populations corresponding to these subsets is the same as that in the population described by the full dataset, but in all cases, the most likely direction of the effect is positive. Comorbidity data were not available for the full dataset, a sub-analysis on those cases where it could be linked indicated that comorbidities did not substantially affect relative severity estimates (S3 Appendix). Model estimates from severity models from all subsets can be found in S3–S5 Tables.

[Figure omitted. See PDF.]

Clinical severity was measured on a four-level ordinal scale based on the level of respiratory support received for 1454 patients stratified by age group; death, invasive or non-invasive ventilatory support including high flow nasal cannulae (IV/NIV/HFNC), supplemental oxygen delivered by low flow mask devices or nasal cannulae, and no respiratory support.

Bernoulli models looking at sequential severity categories provided weak evidence that the proportional odds assumption of the cumulative logistic model was violated. The odds ratios for the no oxygen versus low flow oxygen, and low flow oxygen versus IV/NIV/HFNC were similar to those estimated under the cumulative model (posterior median odds ratio for no oxygen versus low flow oxygen: 1.77, CI: 1.12–2.80; posterior median odds ratio for low flow oxygen versus IV/NIV/HFNC: 1.26, CI: 0.43–3.67) but with correspondingly higher posterior variances given the smaller sample size. The odds ratios for the IV/NIV/HFNC versus death model suggested that the preponderance of evidence was in favour of Alpha infection associated with lower risk of death, conditional on having received IV, NIV or HFNC (posterior median odds ratio: 0.64, CI: 0.22–1.90). However, the credible intervals here are wide, given the sample size, and do include the estimated global effect. A similar but more extreme effect was observed for the effect of biological sex, with male sex being associated with more severe outcomes for the first two sequential category models (posterior median odds ratio for no oxygen versus low flow oxygen: 1.32, CI: 0.96–1.80; posterior median odds ratio for low flow oxygen versus IV/NIV/HFNC: 3.10, CI: 1.37–7.08), but withless severe outcomes for the last (posterior odds ratio for IV/NIV/HFNC vs death: 0.62, CI: 0.19–099). Given other research on the topic has consistently identified male sex as a risk factor, this potentially indicates the existence of an important unmeasured confounder only relevant for those requiring invasive ventilation, non-invasive ventilation or high flow nasal cannula oxygen.

Estimates of the severity across the phylogeny are visible in Fig 3; see S2 Appendix for more discussion of this analysis. An analysis including comorbidities for the subset of patients where they were available implied that the inclusion of comorbidities had no impact on the results obtained, see S1 and S3 Appendices.

[Figure omitted. See PDF.]

Estimated severities for each viral isolate are means and 95% credible intervals of the linear predictor change under infection with that viral genotype from the phylogenetic random effect in the cumulative severity model under a Brownian motion model of evolution. This model constrains genetically identical isolates to have identical effects, so changes should be interpreted across the phylogeny rather than between closely related isolates which necessarily have similar estimated severities. The dataset was downsampled to 100 random samples for this figure to aid readability. Figure was generated using ggtree [31].

We also found that the Alpha variant was associated with lower Ct values than infection with pre-Alpha variants (posterior median Ct change: -2.46, 95% CI: -4.22 - -0.70) as previously observed [8]. Model estimates for all parameters can be found in S6 Table.

We found no evidence that the Alpha variant was associated with longer hospital stays after controlling for age and sex (HR: -0.02; 95% CI: -0.23–0.20; p = 0.89).

Discussion

In this analysis of hospitalised and community patients with Alpha variant and pre-Alpha variant SARS-CoV-2 infection, carried out as the Alpha variant became dominant in Scotland, we provide evidence of increased clinical severity associated with this variant at this time, after adjusting for age, sex, geography and calendar time, as well as testing for sensitivity to number of comorbidities. This was observed across all adult age groups, incorporating the spectrum of COVID-19 disease; from no requirement for supportive care, to supplemental oxygen requirement, the need for invasive or non-invasive ventilation, and to death. This analysis is the first to assess the full clinical severity spectrum of confirmed Alpha variant infection in both community and hospitalised cases in relation to other prevalent lineages circulating during the same time period.

Our study supports the community testing analyses that have reported an increased 28-day mortality associated with SGTF as a proxy for Alpha variant status [8–10]. Smaller studies found no effect of lineage on various measures of severity [15–17], but these were studies of patients already admitted to hospital and therefore would not pick up the granular detail of increasing disease severity resulting in a need for increasing levels of respiratory support and consequently admission to hospital.

The association between higher viral load, higher transmission and lineage may reflect changes in the biology of the virus; for example, the Alpha variant asparagine (N) to tyrosine (Y) mutation at position 501 of the spike protein receptor binding domain (RBD) was associated with an increase in binding affinity to the human ACE2 receptor [32]. In addition, a deletion at position 69–70 may have increased virus infectivity [33]. The P681H mutation found at the furin cleavage site is associated with more efficient furin cleavage, enhancing cell entry [34]. An alternative explanation for the higher viral loads observed in Alpha variant infection may be that clinical presentation occurs earlier in the illness. Further modelling, animal experiments and studies in healthy volunteers may help to unravel the mechanisms behind this phenomenon.

Our data indicate an association between the Alpha variant and an increased risk of requiring supplemental oxygen and ventilation compared to per-Alpha variants. These two factors are critical determinants of healthcare capacity during a period of high incidence of SARS-CoV-2 infection, and this illustrates the importance for countries, in particular those with less robust health care systems and lower vaccination rates of factoring the requirement for supportive treatment into models of clinical severity and pandemic response decision planning for future SARS-CoV-2 variants of concern. This granular analysis of disease severity based on genomic confirmation of diagnosis should be used as a baseline study for clinical severity analysis of the inevitable future variants of concern.

There are some limitations to our study. Our dataset is drawn from first-line local NHS diagnostic (Pillar 1) testing which over-represents patients presenting for hospital care (59%) while those sampled in the community represented 41% of the dataset. The effect of working in the healthcare sector on severity, driven by systematically different exposures faced by frontline caregivers, could not be adjusted for, due to incompleteness of the data regarding this variable. Further, the analysis dataset employed a non-standardised approach to sampling across the study period as sequencing was carried out both as systematic randomised national surveillance and sampling following outbreaks of interest. Additionally, we did not have information about the vaccination status of the individuals in the study. However, our inability to adjust for this variable is not likely to have had a great impact on our conclusions, as, at the time of the study, the vaccination campaign had recently begun, with only over 75 year olds and high-risk groups eligible. Finally, the cumulative model used and the usage of a single (not location varying) spine for the effect of time in this analysis assumes a homogenous application of therapeutic intervention across the population. Despite these limitations, our results remain consistent with previous work on the mortality of Alpha, and this study provides new information regarding differences in infection severity.

In summary, the Alpha variant was found to be associated with a rapid increase in COVID-19 cases in Scotland in the winter of 2020/21, and an increased risk of severe infection requiring supportive care. This has implications for planning for future variant driven waves of infection, especially in countries with low vaccine uptake or if variants evolve with significant vaccine-escape. Our study has shown the value of the collection of higher resolution patient outcome data linked to genetic sequences when looking for clinically relevant differences between viral variants.

Supporting information

S1 Table. Characteristic mutations of the Alpha variant.

https://doi.org/10.1371/journal.pone.0284187.s001

(DOCX)

S2 Table. Full lineage characterisation of clinical severity dataset.

https://doi.org/10.1371/journal.pone.0284187.s002

(DOCX)

S3 Table. Parameter estimates (on the linear predictor scale) from the severity model from the full dataset.

https://doi.org/10.1371/journal.pone.0284187.s003

(DOCX)

S4 Table. Parameter estimates (on the linear predictor scale) from the severity model from the data subset excluding patients in nursing homes.

https://doi.org/10.1371/journal.pone.0284187.s004

(DOCX)

S5 Table. Parameter estimates (on the linear predictor scale) from the severity model from the data subset only including hospitalised patients.

https://doi.org/10.1371/journal.pone.0284187.s005

(DOCX)

S6 Table. Parameter estimates from the Ct value model.

https://doi.org/10.1371/journal.pone.0284187.s006

(DOCX)

S1 Appendix. Further methods.

https://doi.org/10.1371/journal.pone.0284187.s007

(DOCX)

S2 Appendix. Phylogenetic severity model.

https://doi.org/10.1371/journal.pone.0284187.s008

(DOCX)

S3 Appendix. Comorbidities.

https://doi.org/10.1371/journal.pone.0284187.s009

(DOCX)

Acknowledgments

We would like to thank all NHS staff that looked after patients during the COVID-19 pandemic in Scotland. The authors would like to acknowledge that this work uses data provided by patients and collected by the National Health Service (NHS) as part of their care and support. The authors would also like to acknowledge the work of the West of Scotland Safe Haven team in supporting extractions and linkage to de-identified NHS patient datasets. The authors would also like to acknowledge the work of the COG-UK consortium whose members are listed below:

Dr Samuel C Robson PhD ^{13, 84}, Dr Thomas R Connor PhD ^{11, 74}, Prof Nicholas J Loman PhD ⁴³, Dr Tanya Golubchik PhD ⁵, Dr Rocio T Martinez Nunez PhD ⁴⁶, Dr David Bonsall PhD ⁵, Prof Andrew Rambaut DPhil ¹⁰⁴, Dr Luke B Snell MSc, MBBS ¹², Rich Livett MSc ¹¹⁶, Dr Catherine Ludden PhD ^{20, 70}, Dr Sally Corden PhD ⁷⁴, Dr Eleni Nastouli FRCPath ^{96, 95, 30}, Dr Gaia Nebbia PhD, FRCPath ¹², Ian Johnston BSc ¹¹⁶, Prof Katrina Lythgoe PhD ⁵, Dr M. Estee Torok FRCP ^{19, 20}, Prof Ian G Goodfellow PhD ²⁴, Dr Jacqui A Prieto PhD ^{97, 82}, Dr Kordo Saeed MD, FRCPath ^{97, 83}, Dr David K Jackson PhD ¹¹⁶, Dr Catherine Houlihan PhD ^{96, 94}, Dr Dan Frampton PhD ^{94, 95}, Dr William L Hamilton PhD ¹⁹, Dr Adam A Witney PhD ⁴¹, Dr Giselda Bucca PhD ¹⁰¹, Dr Cassie F Pope PhD^{40, 41}, Dr Catherine Moore PhD ⁷⁴, Prof Emma C Thomson PhD, FRCP ⁵³, Dr Teresa Cutino-Moguel PhD ², Dr Ewan M Harrison PhD ^{116, 102}, Prof Colin P Smith PhD ¹⁰¹, Fiona Rogan BSc ⁷⁷, Shaun M Beckwith MSc ⁶, Abigail Murray Degree ⁶, Dawn Singleton HNC ⁶, Dr Kirstine Eastick PhD, FRCPath ³⁷, Dr Liz A Sheridan PhD ⁹⁸, Paul Randell MSc, PgD ⁹⁹, Dr Leigh M Jackson PhD ¹⁰⁵, Dr Cristina V Ariani PhD ¹¹⁶, Dr Sónia Gonçalves PhD ¹¹⁶, Dr Derek J Fairley PhD ^{3, 77}, Prof Matthew W Loose PhD ¹⁸, Joanne Watkins MSc ⁷⁴, Dr Samuel Moses MD ^{25, 106}, Dr Sam Nicholls PhD ⁴³, Dr Matthew Bull PhD ⁷⁴, Dr Roberto Amato PhD ¹¹⁶, Prof Darren L Smith PhD ^{36, 65, 66}, Prof David M Aanensen PhD ^{14, 116}, Dr Jeffrey C Barrett PhD ¹¹⁶, Dr Beatrix Kele PhD ², Dr Dinesh Aggarwal MRCP^{20, 116, 70}, Dr James G Shepherd MBCHB, MRCP ⁵³, Dr Martin D Curran PhD ⁷¹, Dr Surendra Parmar PhD ⁷¹, Dr Matthew D Parker PhD ¹⁰⁹, Dr Catryn Williams PhD ⁷⁴, Dr Sharon Glaysher PhD ⁶⁸, Dr Anthony P Underwood PhD ^{14, 116}, Dr Matthew Bashton PhD ^{36, 65}, Dr Nicole Pacchiarini PhD ⁷⁴, Dr Katie F Loveson PhD ⁸⁴, Matthew Byott MSc ^{95, 96}, Dr Alessandro M Carabelli PhD ²⁰, Dr Kate E Templeton PhD ^{56, 104}, Prof Sharon J Peacock PhD ^{20, 70*}, Dr Thushan I de Silva PhD ¹⁰⁹, Dr Dennis Wang PhD ¹⁰⁹, Dr Cordelia F Langford PhD ¹¹⁶, John Sillitoe BEng ¹¹⁶, Prof Rory N Gunson PhD, FRCPath ⁵⁵, Dr Simon Cottrell PhD ⁷⁴, Dr Justin O’Grady PhD ^{75, 103}, Prof Dominic Kwiatkowski PhD ^{116, 108}, Dr Patrick J Lillie PhD, FRCP ³⁷, Dr Nicholas Cortes MBCHB ³³, Dr Nathan Moore MBCHB ³³, Dr Claire Thomas DPhil ³³, Phillipa J Burns MSc, DipRCPath ³⁷, Dr Tabitha W Mahungu FRCPath ⁸⁰, Steven Liggett BSc ⁸⁶, Angela H Beckett MSc ^{13, 81}, Prof Matthew TG Holden PhD ⁷³, Dr Lisa J Levett PhD ³⁴, Dr Husam Osman PhD ^{70, 35}, Dr Mohammed O Hassan-Ibrahim PhD, FRCPath ⁹⁹, Dr David A Simpson PhD ⁷⁷, Dr Meera Chand PhD ⁷², Prof Ravi K Gupta PhD ¹⁰², Prof Alistair C Darby PhD ¹⁰⁷, Prof Steve Paterson PhD ¹⁰⁷, Prof Oliver G Pybus DPhil ²³, Dr Erik M Volz PhD ³⁹, Prof Daniela de Angelis PhD ⁵², Prof David L Robertson PhD ⁵³, Dr Andrew J Page PhD ⁷⁵, Dr Inigo Martincorena PhD ¹¹⁶, Dr Louise Aigrain PhD ¹¹⁶, Dr Andrew R Bassett PhD ¹¹⁶, Dr Nick Wong DPhil, MRCP, FRCPath ⁵⁰, Dr Yusri Taha MD, PhD ⁸⁹, Michelle J Erkiert BA ⁹⁹, Dr Michael H Spencer Chapman MBBS ^{116, 102}, Dr Rebecca Dewar PhD ⁵⁶, Martin P McHugh MSc ^{56, 111}, Siddharth Mookerjee MPH ^{38, 57}, Stephen Aplin ⁹⁷, Matthew Harvey ⁹⁷, Thea Sass ⁹⁷, Dr Helen Umpleby FRCP ⁹⁷, Helen Wheeler ⁹⁷, Dr James P McKenna PhD ³, Dr Ben Warne MRCP ⁹, Joshua F Taylor MSc ²², Yasmin Chaudhry BSc ²⁴, Rhys Izuagbe ²⁴, Dr Aminu S Jahun PhD ²⁴, Dr Gregory R Young PhD ^{36, 65}, Dr Claire McMurray PhD ⁴³, Dr Clare M McCann PhD ^{65, 66}, Dr Andrew Nelson PhD ^{65, 66}, Scott Elliott ⁶⁸, Hannah Lowe MSc ²⁵, Dr Anna Price PhD ¹¹, Matthew R Crown BSc ⁶⁵, Dr Sara Rey PhD ⁷⁴, Dr Sunando Roy PhD ⁹⁶, Dr Ben Temperton PhD ¹⁰⁵, Dr Sharif Shaaban PhD ⁷³, Dr Andrew R Hesketh PhD ¹⁰¹, Dr Kenneth G Laing PhD⁴¹, Dr Irene M Monahan PhD ⁴¹, Dr Judith Heaney PhD ^{95, 96, 34}, Dr Emanuela Pelosi FRCPath ⁹⁷, Siona Silviera MSc ⁹⁷, Dr Eleri Wilson-Davies MD, FRCPath ⁹⁷, Dr Helen Fryer PhD ⁵, Dr Helen Adams PhD ⁴, Dr Louis du Plessis PhD ²³, Dr Rob Johnson PhD ³⁹, Dr William T Harvey PhD ^{53, 42}, Dr Joseph Hughes PhD ⁵³, Dr Richard J Orton PhD ⁵³, Dr Lewis G Spurgin PhD ⁵⁹, Dr Yann Bourgeois PhD ⁸¹, Dr Chris Ruis PhD ¹⁰², Áine O’Toole MSc ¹⁰⁴, Marina Gourtovaia MSc ¹¹⁶, Dr Theo Sanderson PhD ¹¹⁶, Dr Christophe Fraser PhD ⁵, Dr Jonathan Edgeworth PhD, FRCPath ¹², Prof Judith Breuer MD ^{96, 29}, Dr Stephen L Michell PhD ¹⁰⁵, Prof John A Todd PhD ¹¹⁵, Michaela John BSc ¹⁰, Dr David Buck PhD ¹¹⁵, Dr Kavitha Gajee MBBS, FRCPath ³⁷, Dr Gemma L Kay PhD ⁷⁵, David Heyburn ⁷⁴, Dr Themoula Charalampous PhD ^{12, 46}, Adela Alcolea-Medina ^{32, 112}, Katie Kitchman BSc ³⁷, Prof Alan McNally PhD ^{43, 93}, David T Pritchard MSc, CSci ⁵⁰, Dr Samir Dervisevic FRCPath ⁵⁸, Dr Peter Muir PhD ⁷⁰, Dr Esther Robinson PhD ^{70, 35}, Dr Barry B Vipond PhD ⁷⁰, Newara A Ramadan MSc, CSci, FIBMS ⁷⁸, Dr Christopher Jeanes MBBS ⁹⁰, Danni Weldon BSc ¹¹⁶, Jana Catalan MSc ¹¹⁸, Neil Jones MSc ¹¹⁸, Dr Ana da Silva Filipe PhD ⁵³, Dr Chris Williams MBBS ⁷⁴, Marc Fuchs BSc ⁷⁷, Dr Julia Miskelly PhD ⁷⁷, Dr Aaron R Jeffries PhD ¹⁰⁵, Karen Oliver BSc ¹¹⁶, Dr Naomi R Park PhD ¹¹⁶, Amy Ash BSc ¹, Cherian Koshy MSc, CSci, FIBMS ¹, Magdalena Barrow ⁷, Dr Sarah L Buchan PhD ⁷, Dr Anna Mantzouratou PhD ⁷, Dr Gemma Clark PhD ¹⁵, Dr Christopher W Holmes PhD ¹⁶, Sharon Campbell MSc ¹⁷, Thomas Davis MSc ²¹, Ngee Keong Tan MSc ²², Dr Julianne R Brown PhD ²⁹, Dr Kathryn A Harris PhD ^{29, 2}, Stephen P Kidd MSc ³³, Dr Paul R Grant PhD ³⁴, Dr Li Xu-McCrae PhD ³⁵, Dr Alison Cox PhD ^{38, 63}, Pinglawathee Madona ^{38, 63}, Dr Marcus Pond PhD ^{38, 63}, Dr Paul A Randell MBBCh ^{38, 63}, Karen T Withell FIBMS ⁴⁸, Cheryl Williams MSc ⁵¹, Dr Clive Graham MD ⁶⁰, Rebecca Denton-Smith BSc ⁶², Emma Swindells BSc ⁶², Robyn Turnbull BSc ⁶², Dr Tim J Sloan PhD ⁶⁷, Dr Andrew Bosworth PhD ^{70, 35}, Stephanie Hutchings ⁷⁰, Hannah M Pymont MSc ⁷⁰, Dr Anna Casey PhD ⁷⁶, Dr Liz Ratcliffe PhD ⁷⁶, Dr Christopher R Jones PhD ^{79, 105}, Dr Bridget A Knight PhD ^{79, 105}, Dr Tanzina Haque PhD, FRCPath ⁸⁰, Dr Jennifer Hart MRCP ⁸⁰, Dr Dianne Irish-Tavares FRCPath ⁸⁰, Eric Witele MSc ⁸⁰, Craig Mower BA ⁸⁶, Louisa K Watson DipHE ⁸⁶, Jennifer Collins BSc ⁸⁹, Gary Eltringham BSc ⁸⁹, Dorian Crudgington ⁹⁸, Ben Macklin ⁹⁸, Prof Miren Iturriza-Gomara PhD ¹⁰⁷, Dr Anita O Lucaci PhD ¹⁰⁷, Dr Patrick C McClure PhD ¹¹³, Matthew Carlile BSc ¹⁸, Dr Nadine Holmes PhD ¹⁸, Dr Christopher Moore PhD ¹⁸, Dr Nathaniel Storey PhD ²⁹, Dr Stefan Rooke PhD ⁷³, Dr Gonzalo Yebra PhD ⁷³, Dr Noel Craine DPhil ⁷⁴, Malorie Perry MSc ⁷⁴, Dr Nabil-Fareed Alikhan PhD ⁷⁵, Dr Stephen Bridgett PhD ⁷⁷, Kate F Cook MScR ⁸⁴, Christopher Fearn MSc ⁸⁴, Dr Salman Goudarzi PhD ⁸⁴, Prof Ronan A Lyons MD ⁸⁸, Dr Thomas Williams MD ¹⁰⁴, Dr Sam T Haldenby PhD ¹⁰⁷, Jillian Durham BSc ¹¹⁶, Dr Steven Leonard PhD ¹¹⁶, Robert M Davies MA (Cantab) ¹¹⁶, Dr Rahul Batra MD ¹², Beth Blane BSc ²⁰, Dr Moira J Spyer PhD ^{30, 95, 96}, Perminder Smith MSc ^{32, 112}, Mehmet Yavus ^{85, 109}, Dr Rachel J Williams PhD ⁹⁶, Dr Adhyana IK Mahanama MD ⁹⁷, Dr Buddhini Samaraweera MD ⁹⁷, Sophia T Girgis MSc ¹⁰², Samantha E Hansford CSci ¹⁰⁹, Dr Angie Green PhD ¹¹⁵, Dr Charlotte Beaver PhD ¹¹⁶, Katherine L Bellis ^{116, 102}, Matthew J Dorman ¹¹⁶, Sally Kay ¹¹⁶, Liam Prestwood ¹¹⁶, Dr Shavanthi Rajatileka PhD ¹¹⁶, Dr Joshua Quick PhD ⁴³, Radoslaw Poplawski BSc ⁴³, Dr Nicola Reynolds PhD ⁸, Andrew Mack MPhil ¹¹, Dr Arthur Morriss PhD ¹¹, Thomas Whalley BSc ¹¹, Bindi Patel BSc ¹², Dr Iliana Georgana PhD ²⁴, Dr Myra Hosmillo PhD ²⁴, Malte L Pinckert MPhil ²⁴, Dr Joanne Stockton PhD ⁴³, Dr John H Henderson PhD ⁶⁵, Amy Hollis HND ⁶⁵, Dr William Stanley PhD ⁶⁵, Dr Wen C Yew PhD ⁶⁵, Dr Richard Myers PhD ⁷², Dr Alicia Thornton PhD ⁷², Alexander Adams BSc ⁷⁴, Tara Annett BSc ⁷⁴, Dr Hibo Asad PhD ⁷⁴, Alec Birchley MSc ⁷⁴, Jason Coombes BSc ⁷⁴, Johnathan M Evans MSc ⁷⁴, Laia Fina ⁷⁴, Bree Gatica-Wilcox MPhil ⁷⁴, Lauren Gilbert ⁷⁴, Lee Graham BSc ⁷⁴, Jessica Hey BSc ⁷⁴, Ember Hilvers MPH ⁷⁴, Sophie Jones MSc ⁷⁴, Hannah Jones ⁷⁴, Sara Kumziene-Summerhayes MSc ⁷⁴, Dr Caoimhe McKerr PhD ⁷⁴, Jessica Powell BSc ⁷⁴, Georgia Pugh ⁷⁴, Sarah Taylor ⁷⁴, Alexander J Trotter MRes ⁷⁵, Charlotte A Williams BSc ⁹⁶, Leanne M Kermack MSc ¹⁰², Benjamin H Foulkes MSc ¹⁰⁹, Marta Gallis MSc ¹⁰⁹, Hailey R Hornsby MSc ¹⁰⁹, Stavroula F Louka MSc ¹⁰⁹, Dr Manoj Pohare PhD ¹⁰⁹, Paige Wolverson MSc ¹⁰⁹, Peijun Zhang MSc ¹⁰⁹, George MacIntyre-Cockett BSc ¹¹⁵, Amy Trebes MSc ¹¹⁵, Dr Robin J Moll PhD ¹¹⁶, Lynne Ferguson MSc ¹¹⁷, Dr Emily J Goldstein PhD ¹¹⁷, Dr Alasdair Maclean PhD ¹¹⁷, Dr Rachael Tomb PhD ¹¹⁷, Dr Igor Starinskij MSc, MRCP ⁵³, Laura Thomson BSc ⁵, Joel Southgate MSc ^{11, 74}, Dr Moritz UG Kraemer DPhil ²³, Dr Jayna Raghwani PhD ²³, Dr Alex E Zarebski PhD ²³, Olivia Boyd MSc ³⁹, Lily Geidelberg MSc ³⁹, Dr Chris J Illingworth PhD ⁵², Dr Chris Jackson PhD ⁵², Dr David Pascall PhD ⁵², Dr Sreenu Vattipally PhD ⁵³, Timothy M Freeman MPhil ¹⁰⁹, Dr Sharon N Hsu PhD ¹⁰⁹, Dr Benjamin B Lindsey MRCP ¹⁰⁹, Dr Keith James PhD ¹¹⁶, Kevin Lewis ¹¹⁶, Gerry Tonkin-Hill ¹¹⁶, Dr Jaime M Tovar-Corona PhD ¹¹⁶, MacGregor Cox MSci ²⁰, Dr Khalil Abudahab PhD ^{14, 116}, Mirko Menegazzo ¹⁴, Ben EW Taylor MEng ^{14, 116}, Dr Corin A Yeats PhD ¹⁴, Afrida Mukaddas BTech ⁵³, Derek W Wright MSc ⁵³, Dr Leonardo de Oliveira Martins PhD ⁷⁵, Dr Rachel Colquhoun DPhil ¹⁰⁴, Verity Hill ¹⁰⁴, Dr Ben Jackson PhD ¹⁰⁴, Dr JT McCrone PhD ¹⁰⁴, Dr Nathan Medd PhD ¹⁰⁴, Dr Emily Scher PhD ¹⁰⁴, Jon-Paul Keatley ¹¹⁶, Dr Tanya Curran PhD ³, Dr Sian Morgan FRCPath ¹⁰, Prof Patrick Maxwell PhD ²⁰, Prof Ken Smith PhD ²⁰, Dr Sahar Eldirdiri MBBS, MSc, FRCPath ²¹, Anita Kenyon MSc ²¹, Prof Alison H Holmes MD ^{38, 57}, Dr James R Price PhD ^{38, 57}, Dr Tim Wyatt PhD ⁶⁹, Dr Alison E Mather PhD ⁷⁵, Dr Timofey Skvortsov PhD ⁷⁷, Prof John A Hartley PhD ⁹⁶, Prof Martyn Guest PhD ¹¹, Dr Christine Kitchen PhD ¹¹, Dr Ian Merrick PhD ¹¹, Robert Munn BSc ¹¹, Dr Beatrice Bertolusso Degree ³³, Dr Jessica Lynch MBCHB ³³, Dr Gabrielle Vernet MBBS ³³, Stuart Kirk MSc ³⁴, Dr Elizabeth Wastnedge MD ⁵⁶, Dr Rachael Stanley PhD ⁵⁸, Giles Idle ⁶⁴, Dr Declan T Bradley PhD ^{69, 77}, Nicholas F Killough MSc ⁶⁹, Dr Jennifer Poyner MD ⁷⁹, Matilde Mori BSc ¹¹⁰, Owen Jones BSc ¹¹, Victoria Wright BSc ¹⁸, Ellena Brooks MA ²⁰, Carol M Churcher BSc ²⁰, Dr Laia Delgado Callico PhD ²⁰, Mireille Fragakis HND ²⁰, Dr Katerina Galai PhD ^{20, 70}, Dr Andrew Jermy PhD ²⁰, Sarah Judges BA ²⁰, Anna Markov BSc ²⁰, Georgina M McManus BSc ²⁰, Kim S Smith ²⁰, Peter M D Thomas-McEwen MSc ²⁰, Dr Elaine Westwick PhD ²⁰, Dr Stephen W Attwood PhD ²³, Dr Frances Bolt PhD ^{38, 57}, Dr Alisha Davies PhD ⁷⁴, Elen De Lacy MPH ⁷⁴, Fatima Downing ⁷⁴, Sue Edwards ⁷⁴, Lizzie Meadows MA ⁷⁵, Sarah Jeremiah MSc ⁹⁷, Dr Nikki Smith PhD ¹⁰⁹, Luke Foulser ¹¹⁶, Amita Patel BSc ¹², Dr Louise Berry PhD ¹⁵, Dr Tim Boswell PhD ¹⁵, Dr Vicki M Fleming PhD ¹⁵, Dr Hannah C Howson-Wells PhD ¹⁵, Dr Amelia Joseph PhD ¹⁵, Manjinder Khakh ¹⁵, Dr Michelle M Lister PhD ¹⁵, Paul W Bird MSc, MRes ¹⁶, Karlie Fallon ¹⁶, Thomas Helmer ¹⁶, Dr Claire L McMurray PhD ¹⁶, Mina Odedra BSc ¹⁶, Jessica Shaw BSc ¹⁶, Dr Julian W Tang PhD ¹⁶, Nicholas J Willford MSc ¹⁶, Victoria Blakey BSc ¹⁷, Dr Veena Raviprakash MD ¹⁷, Nicola Sheriff BSc ¹⁷, Lesley-Anne Williams BSc ¹⁷, Theresa Feltwell MSc ²⁰, Dr Luke Bedford PhD ²⁶, Dr James S Cargill PhD ²⁷, Warwick Hughes MSc ²⁷, Dr Jonathan Moore MD ²⁸, Susanne Stonehouse BSc ²⁸, Laura Atkinson MSc ²⁹, Jack CD Lee MSc ²⁹, Dr Divya Shah PhD ²⁹, Natasha Ohemeng-Kumi MSc ^{32, 112}, John Ramble MSc ^{32, 112}, Jasveen Sehmi MSc ^{32, 112}, Dr Rebecca Williams BMBS ³³, Wendy Chatterton MSc ³⁴, Monika Pusok MSc ³⁴, William Everson MSc ³⁷, Anibolina Castigador IBMS HCPC ⁴⁴, Emily Macnaughton FRCPath ⁴⁴, Dr Kate El Bouzidi MRCP ⁴⁵, Dr Temi Lampejo FRCPath ⁴⁵, Dr Malur Sudhanva FRCPath ⁴⁵, Cassie Breen BSc ⁴⁷, Dr Graciela Sluga MD, MSc ⁴⁸, Dr Shazaad SY Ahmad MSc ^{49, 70}, Dr Ryan P George PhD ⁴⁹, Dr Nicholas W Machin MSc ^{49, 70}, Debbie Binns BSc ⁵⁰, Victoria James BSc ⁵⁰, Dr Rachel Blacow MBCHB ⁵⁵, Dr Lindsay Coupland PhD ⁵⁸, Dr Louise Smith PhD ⁵⁹, Dr Edward Barton MD ⁶⁰, Debra Padgett BSc ⁶⁰, Garren Scott BSc ⁶⁰, Dr Aidan Cross MBCHB ⁶¹, Dr Mariyam Mirfenderesky FRCPath ⁶¹, Jane Greenaway MSc ⁶², Kevin Cole ⁶⁴, Phillip Clarke ⁶⁷, Nichola Duckworth ⁶⁷, Sarah Walsh ⁶⁷, Kelly Bicknell ⁶⁸, Robert Impey MSc ⁶⁸, Dr Sarah Wyllie PhD ⁶⁸, Richard Hopes ⁷⁰, Dr Chloe Bishop PhD ⁷², Dr Vicki Chalker PhD ⁷², Dr Ian Harrison PhD ⁷², Laura Gifford MSc ⁷⁴, Dr Zoltan Molnar PhD ⁷⁷, Dr Cressida Auckland FRCPath ⁷⁹, Dr Cariad Evans PhD ^{85, 109}, Dr Kate Johnson PhD ^{85, 109}, Dr David G Partridge FRCP, FRCPath ^{85, 109}, Dr Mohammad Raza PhD ^{85, 109}, Paul Baker MD ⁸⁶, Prof Stephen Bonner PhD ⁸⁶, Sarah Essex ⁸⁶, Leanne J Murray ⁸⁶, Andrew I Lawton MSc ⁸⁷, Dr Shirelle Burton-Fanning MD ⁸⁹, Dr Brendan AI Payne MD ⁸⁹, Dr Sheila Waugh MD ⁸⁹, Andrea N Gomes MSc ⁹¹, Maimuna Kimuli MSc ⁹¹, Darren R Murray MSc ⁹¹, Paula Ashfield MSc ⁹², Dr Donald Dobie MBCHB ⁹², Dr Fiona Ashford PhD ⁹³, Dr Angus Best PhD ⁹³, Dr Liam Crawford PhD ⁹³, Dr Nicola Cumley PhD ⁹³, Dr Megan Mayhew PhD ⁹³, Dr Oliver Megram PhD ⁹³, Dr Jeremy Mirza PhD ⁹³, Dr Emma Moles-Garcia PhD ⁹³, Dr Benita Percival PhD ⁹³, Megan Driscoll BSc ⁹⁶, Leah Ensell BSc ⁹⁶, Dr Helen L Lowe PhD ⁹⁶, Laurentiu Maftei BSc ⁹⁶, Matteo Mondani MSc ⁹⁶, Nicola J Chaloner BSc ⁹⁹, Benjamin J Cogger BSc ⁹⁹, Lisa J Easton MSc ⁹⁹, Hannah Huckson BSc ⁹⁹, Jonathan Lewis MSc, PgD, FIBMS ⁹⁹, Sarah Lowdon BSc ⁹⁹, Cassandra S Malone MSc ⁹⁹, Florence Munemo BSc ⁹⁹, Manasa Mutingwende MSc ⁹⁹, Roberto Nicodemi BSc ⁹⁹, Olga Podplomyk FD ⁹⁹, Thomas Somassa BSc ⁹⁹, Dr Andrew Beggs PhD ¹⁰⁰, Dr Alex Richter PhD ¹⁰⁰, Claire Cormie ¹⁰², Joana Dias MSc ¹⁰², Sally Forrest BSc ¹⁰², Dr Ellen E Higginson PhD ¹⁰², Mailis Maes MPhil ¹⁰², Jamie Young BSc ¹⁰², Dr Rose K Davidson PhD ¹⁰³, Kathryn A Jackson MSc ¹⁰⁷, Dr Alexander J Keeley MRCP ¹⁰⁹, Prof Jonathan Ball PhD ¹¹³, Timothy Byaruhanga MSc ¹¹³, Dr Joseph G Chappell PhD ¹¹³, Jayasree Dey MSc ¹¹³, Jack D Hill MSc ¹¹³, Emily J Park MSc ¹¹³, Arezou Fanaie MSc ¹¹⁴, Rachel A Hilson MSc ¹¹⁴, Geraldine Yaze MSc ¹¹⁴, Stephanie Lo ¹¹⁶, Safiah Afifi BSc ¹⁰, Robert Beer BSc ¹⁰, Joshua Maksimovic FD ¹⁰, Kathryn McCluggage Masters ¹⁰, Karla Spellman FD ¹⁰, Catherine Bresner BSc ¹¹, William Fuller BSc ¹¹, Dr Angela Marchbank BSc ¹¹, Trudy Workman HNC ¹¹, Dr Ekaterina Shelest PhD ^{13, 81}, Dr Johnny Debebe PhD ¹⁸, Dr Fei Sang PhD ¹⁸, Dr Sarah Francois PhD ²³, Bernardo Gutierrez MSc ²³, Dr Tetyana I Vasylyeva DPhil ²³, Dr Flavia Flaviani PhD ³¹, Dr Manon Ragonnet-Cronin PhD ³⁹, Dr Katherine L Smollett PhD ⁴², Alice Broos BSc ⁵³, Daniel Mair BSc ⁵³, Jenna Nichols BSc ⁵³, Dr Kyriaki Nomikou PhD ⁵³, Dr Lily Tong PhD ⁵³, Ioulia Tsatsani MSc ⁵³, Prof Sarah O’Brien PhD ⁵⁴, Prof Steven Rushton PhD ⁵⁴, Dr Roy Sanderson PhD ⁵⁴, Dr Jon Perkins MBCHB ⁵⁵, Seb Cotton MSc ⁵⁶, Abbie Gallagher BSc ⁵⁶, Dr Elias Allara MD, PhD ^{70, 102}, Clare Pearson MSc ^{70, 102}, Dr David Bibby PhD ⁷², Dr Gavin Dabrera PhD ⁷², Dr Nicholas Ellaby PhD ⁷², Dr Eileen Gallagher PhD ⁷², Dr Jonathan Hubb PhD ⁷², Dr Angie Lackenby PhD ⁷², Dr David Lee PhD ⁷², Nikos Manesis ⁷², Dr Tamyo Mbisa PhD ⁷², Dr Steven Platt PhD ⁷², Katherine A Twohig ⁷², Dr Mari Morgan PhD ⁷⁴, Alp Aydin MSci ⁷⁵, David J Baker BEng ⁷⁵, Dr Ebenezer Foster-Nyarko PhD ⁷⁵, Dr Sophie J Prosolek PhD ⁷⁵, Steven Rudder ⁷⁵, Chris Baxter BSc ⁷⁷, Sílvia F Carvalho MSc ⁷⁷, Dr Deborah Lavin PhD ⁷⁷, Dr Arun Mariappan PhD ⁷⁷, Dr Clara Radulescu PhD ⁷⁷, Dr Aditi Singh PhD ⁷⁷, Miao Tang MD ⁷⁷, Helen Morcrette BSc ⁷⁹, Nadua Bayzid BSc ⁹⁶, Marius Cotic MSc ⁹⁶, Dr Carlos E Balcazar PhD ¹⁰⁴, Dr Michael D Gallagher PhD ¹⁰⁴, Dr Daniel Maloney PhD ¹⁰⁴, Thomas D Stanton BSc ¹⁰⁴, Dr Kathleen A Williamson PhD ¹⁰⁴, Dr Robin Manley PhD ¹⁰⁵, Michelle L Michelsen BSc ¹⁰⁵, Dr Christine M Sambles PhD ¹⁰⁵, Dr David J Studholme PhD ¹⁰⁵, Joanna Warwick-Dugdale BSc ¹⁰⁵, Richard Eccles MSc ¹⁰⁷, Matthew Gemmell MSc ¹⁰⁷, Dr Richard Gregory PhD ¹⁰⁷, Dr Margaret Hughes PhD ¹⁰⁷, Charlotte Nelson MSc ¹⁰⁷, Dr Lucille Rainbow PhD ¹⁰⁷, Dr Edith E Vamos PhD ¹⁰⁷, Hermione J Webster BSc ¹⁰⁷, Dr Mark Whitehead PhD ¹⁰⁷, Claudia Wierzbicki BSc ¹⁰⁷, Dr Adrienn Angyal PhD ¹⁰⁹, Dr Luke R Green PhD ¹⁰⁹, Dr Max Whiteley PhD ¹⁰⁹, Emma Betteridge BSc ¹¹⁶, Dr Iraad F Bronner PhD ¹¹⁶, Ben W Farr BSc ¹¹⁶, Scott Goodwin MSc ¹¹⁶, Dr Stefanie V Lensing PhD ¹¹⁶, Shane A McCarthy ^{116, 102}, Dr Michael A Quail PhD ¹¹⁶, Diana Rajan MSc ¹¹⁶, Dr Nicholas M Redshaw PhD ¹¹⁶, Carol Scott ¹¹⁶, Lesley Shirley MSc ¹¹⁶, Scott AJ Thurston BSc ¹¹⁶, Dr Will Rowe PhD⁴³, Amy Gaskin MSc ⁷⁴, Dr Thanh Le-Viet PhD ⁷⁵, James Bonfield BSc ¹¹⁶, Jennifier Liddle ¹¹⁶ and Andrew Whitwham BSc ¹¹⁶

1 Barking, Havering and Redbridge University Hospitals NHS Trust, 2 Barts Health NHS Trust, 3 Belfast Health & Social Care Trust, 4 Betsi Cadwaladr University Health Board, 5 Big Data Institute, Nuffield Department of Medicine, University of Oxford, 6 Blackpool Teaching Hospitals NHS Foundation Trust, 7 Bournemouth University, 8 Cambridge Stem Cell Institute, University of Cambridge, 9 Cambridge University Hospitals NHS Foundation Trust, 10 Cardiff and Vale University Health Board, 11 Cardiff University, 12 Centre for Clinical Infection and Diagnostics Research, Department of Infectious Diseases, Guy’s and St Thomas’ NHS Foundation Trust, 13 Centre for Enzyme Innovation, University of Portsmouth, 14 Centre for Genomic Pathogen Surveillance, University of Oxford, 15 Clinical Microbiology Department, Queens Medical Centre, Nottingham University Hospitals NHS Trust, 16 Clinical Microbiology, University Hospitals of Leicester NHS Trust, 17 County Durham and Darlington NHS Foundation Trust, 18 Deep Seq, School of Life Sciences, Queens Medical Centre, University of Nottingham, 19 Department of Infectious Diseases and Microbiology, Cambridge University Hospitals NHS Foundation Trust, 20 Department of Medicine, University of Cambridge, 21 Department of Microbiology, Kettering General Hospital, 22 Department of Microbiology, South West London Pathology, 23 Department of Zoology, University of Oxford, 24 Division of Virology, Department of Pathology, University of Cambridge, 25 East Kent Hospitals University NHS Foundation Trust, 26 East Suffolk and North Essex NHS Foundation Trust, 27 East Sussex Healthcare NHS Trust, 28 Gateshead Health NHS Foundation Trust, 29 Great Ormond Street Hospital for Children NHS Foundation Trust, 30 Great Ormond Street Institute of Child Health (GOS ICH), University College London (UCL), 31 Guy’s and St. Thomas’ Biomedical Research Centre, 32 Guy’s and St. Thomas’ NHS Foundation Trust, 33 Hampshire Hospitals NHS Foundation Trust, 34 Health Services Laboratories, 35 Heartlands Hospital, Birmingham, 36 Hub for Biotechnology in the Built Environment, Northumbria University, 37 Hull University Teaching Hospitals NHS Trust, 38 Imperial College Healthcare NHS Trust, 39 Imperial College London, 40 Infection Care Group, St George’s University Hospitals NHS Foundation Trust, 41 Institute for Infection and Immunity, St George’s University of London, 42 Institute of Biodiversity, Animal Health & Comparative Medicine, 43 Institute of Microbiology and Infection, University of Birmingham, 44 Isle of Wight NHS Trust, 45 King’s College Hospital NHS Foundation Trust, 46 King’s College London, 47 Liverpool Clinical Laboratories, 48 Maidstone and Tunbridge Wells NHS Trust, 49 Manchester University NHS Foundation Trust, 50 Microbiology Department, Buckinghamshire Healthcare NHS Trust, 51 Microbiology, Royal Oldham Hospital, 52 MRC Biostatistics Unit, University of Cambridge, 53 MRC-University of Glasgow Centre for Virus Research, 54 Newcastle University, 55 NHS Greater Glasgow and Clyde, 56 NHS Lothian, 57 NIHR Health Protection Research Unit in HCAI and AMR, Imperial College London, 58 Norfolk and Norwich University Hospitals NHS Foundation Trust, 59 Norfolk County Council, 60 North Cumbria Integrated Care NHS Foundation Trust, 61 North Middlesex University Hospital NHS Trust, 62 North Tees and Hartlepool NHS Foundation Trust, 63 North West London Pathology, 64 Northumbria Healthcare NHS Foundation Trust, 65 Northumbria University, 66 NU-OMICS, Northumbria University, 67 Path Links, Northern Lincolnshire and Goole NHS Foundation Trust, 68 Portsmouth Hospitals University NHS Trust, 69 Public Health Agency, Northern Ireland, 70 Public Health England, 71 Public Health England, Cambridge, 72 Public Health England, Colindale, 73 Public Health Scotland, 74 Public Health Wales, 75 Quadram Institute Bioscience, 76 Queen Elizabeth Hospital, Birmingham, 77 Queen’s University Belfast, 78 Royal Brompton and Harefield Hospitals, 79 Royal Devon and Exeter NHS Foundation Trust, 80 Royal Free London NHS Foundation Trust, 81 School of Biological Sciences, University of Portsmouth, 82 School of Health Sciences, University of Southampton, 83 School of Medicine, University of Southampton, 84 School of Pharmacy & Biomedical Sciences, University of Portsmouth, 85 Sheffield Teaching Hospitals NHS Foundation Trust, 86 South Tees Hospitals NHS Foundation Trust, 87 Southwest Pathology Services, 88 Swansea University, 89 The Newcastle upon Tyne Hospitals NHS Foundation Trust, 90 The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust, 91 The Royal Marsden NHS Foundation Trust, 92 The Royal Wolverhampton NHS Trust, 93 Turnkey Laboratory, University of Birmingham, 94 University College London Division of Infection and Immunity, 95 University College London Hospital Advanced Pathogen Diagnostics Unit, 96 University College London Hospitals NHS Foundation Trust, 97 University Hospital Southampton NHS Foundation Trust, 98 University Hospitals Dorset NHS Foundation Trust, 99 University Hospitals Sussex NHS Foundation Trust, 100 University of Birmingham, 101 University of Brighton, 102 University of Cambridge, 103 University of East Anglia, 104 University of Edinburgh, 105 University of Exeter, 106 University of Kent, 107 University of Liverpool, 108 University of Oxford, 109 University of Sheffield, 110 University of Southampton, 111 University of St Andrews, 112 Viapath, Guy’s and St Thomas’ NHS Foundation Trust, and King’s College Hospital NHS Foundation Trust, 113 Virology, School of Life Sciences, Queens Medical Centre, University of Nottingham, 114 Watford General Hospital, 115 Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, 116 Wellcome Sanger Institute, 117 West of Scotland Specialist Virology Centre, NHS Greater Glasgow and Clyde, 118 Whittington Health NHS Trust

*Consortium lead–email: [email protected]

Citation: Pascall DJ, Vink E, Blacow R, Bulteel N, Campbell A, Campbell R, et al. (2023) The SARS-CoV-2 Alpha variant was associated with increased clinical severity of COVID-19 in Scotland: A genomics-based retrospective cohort analysis. PLoS ONE 18(4): e0284187. https://doi.org/10.1371/journal.pone.0284187

About the Authors:

David J. Pascall

Contributed equally to this work with: David J. Pascall, Elen Vink

Roles: Data curation, Formal analysis, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing

Affiliations: MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom, Joint Universities Pandemic and Epidemiological Research (JUNIPER) Consortium, United Kingdom

ORICD: https://orcid.org/0000-0002-7543-0860

Elen Vink

Contributed equally to this work with: David J. Pascall, Elen Vink

Roles: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Writing – review & editing

Affiliations: MRC–University of Glasgow Centre for Virus Research (CVR), Glasgow, United Kingdom, NHS Lothian, Edinburgh, United Kingdom

ORICD: https://orcid.org/0000-0001-8535-6214

Rachel Blacow

Roles: Conceptualization, Investigation, Writing – review & editing

Affiliations: MRC–University of Glasgow Centre for Virus Research (CVR), Glasgow, United Kingdom, NHS Greater Glasgow and Clyde, Glasgow, United Kingdom

Naomi Bulteel

Roles: Investigation, Writing – review & editing

Affiliation: NHS Fife, Kirkcaldy, Fife, United Kingdom

Alasdair Campbell

Roles: Investigation, Writing – review & editing

Affiliation: NHS Lothian, Edinburgh, United Kingdom

Robyn Campbell

Roles: Investigation, Writing – review & editing

Affiliation: NHS Lothian, Edinburgh, United Kingdom

Sarah Clifford

Roles: Investigation, Writing – review & editing

Affiliation: NHS Lothian, Edinburgh, United Kingdom

Chris Davis

Roles: Conceptualization, Investigation, Methodology, Writing – review & editing

Affiliation: MRC–University of Glasgow Centre for Virus Research (CVR), Glasgow, United Kingdom

Ana da Silva Filipe

Roles: Conceptualization, Data curation, Investigation, Methodology, Writing – review & editing

Affiliation: MRC–University of Glasgow Centre for Virus Research (CVR), Glasgow, United Kingdom

Noha El Sakka

Roles: Investigation, Writing – review & editing

Affiliation: NHS Grampian, Aberdeen, United Kingdom

ORICD: https://orcid.org/0000-0003-0225-826X

Ludmila Fjodorova

Roles: Investigation, Writing – review & editing

Affiliation: NHS Greater Glasgow and Clyde, Glasgow, United Kingdom

Ruth Forrest

Roles: Investigation, Writing – review & editing

Affiliation: NHS Fife, Kirkcaldy, Fife, United Kingdom

Emily Goldstein

Roles: Investigation, Writing – review & editing

Affiliation: NHS Greater Glasgow and Clyde, Glasgow, United Kingdom

Rory Gunson

Roles: Investigation, Writing – review & editing

Affiliation: NHS Greater Glasgow and Clyde, Glasgow, United Kingdom

John Haughney

Roles: Project administration, Writing – review & editing

Affiliation: NHS Greater Glasgow and Clyde, Glasgow, United Kingdom

Matthew T. G. Holden

Roles: Data curation, Methodology, Writing – review & editing

Affiliations: Public Health Scotland, Edinburgh, United Kingdom, School of Medicine, University of St Andrews, St Andrews, Fife, United Kingdom

Patrick Honour

Roles: Investigation, Writing – review & editing

Affiliation: NHS Borders, Melrose, Scottish Borders, United Kingdom

Joseph Hughes

Roles: Formal analysis, Methodology, Visualization, Writing – review & editing

Affiliation: MRC–University of Glasgow Centre for Virus Research (CVR), Glasgow, United Kingdom

ORICD: https://orcid.org/0000-0003-2556-2563

Edward James

Roles: Investigation, Writing – review & editing

Affiliation: NHS Borders, Melrose, Scottish Borders, United Kingdom

Tim Lewis

Roles: Investigation, Writing – review & editing

Affiliation: NHS Lothian, Edinburgh, United Kingdom

Samantha Lycett

Roles: Formal analysis, Methodology, Visualization, Writing – review & editing

Affiliation: The Roslin Institute, University of Edinburgh, Midlothian, United Kingdom

ORICD: https://orcid.org/0000-0003-3159-596X

Oscar MacLean

Roles: Methodology, Writing – review & editing

Affiliation: MRC–University of Glasgow Centre for Virus Research (CVR), Glasgow, United Kingdom

Martin McHugh

Roles: Investigation, Writing – review & editing

Affiliation: NHS Lothian, Edinburgh, United Kingdom

ORICD: https://orcid.org/0000-0002-0370-3700

Guy Mollett

Roles: Conceptualization, Data curation, Investigation, Methodology, Writing – original draft, Writing – review & editing

Affiliations: MRC–University of Glasgow Centre for Virus Research (CVR), Glasgow, United Kingdom, NHS Greater Glasgow and Clyde, Glasgow, United Kingdom

Yusuke Onishi

Roles: Investigation, Writing – review & editing

Affiliation: NHS Grampian, Aberdeen, United Kingdom

Ben Parcell

Roles: Investigation, Writing – review & editing

Affiliation: School of Life Sciences, University of Dundee, Dundee, United Kingdom

Surajit Ray

Roles: Methodology, Writing – review & editing

Affiliation: School of Mathematics and Statistics, University of Glasgow, Glasgow, United Kingdom

ORICD: https://orcid.org/0000-0003-3965-8136

David L. Robertson

Roles: Conceptualization, Methodology, Writing – review & editing

Affiliation: MRC–University of Glasgow Centre for Virus Research (CVR), Glasgow, United Kingdom

Sharif Shabaan

Roles: Data curation, Methodology, Writing – review & editing

Affiliation: Public Health Scotland, Edinburgh, United Kingdom

ORICD: https://orcid.org/0000-0001-8293-9481

James G. Shepherd

Roles: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing

Affiliation: MRC–University of Glasgow Centre for Virus Research (CVR), Glasgow, United Kingdom

ORICD: https://orcid.org/0000-0003-3915-048X

Katherine Smollett

Roles: Investigation, Writing – review & editing

Affiliation: MRC–University of Glasgow Centre for Virus Research (CVR), Glasgow, United Kingdom

Kate Templeton

Roles: Investigation, Writing – review & editing

Affiliation: NHS Lothian, Edinburgh, United Kingdom

Elizabeth Wastnedge

Roles: Investigation, Writing – review & editing

Affiliation: NHS Lothian, Edinburgh, United Kingdom

Craig Wilkie

Roles: Methodology, Writing – review & editing

Affiliation: School of Mathematics and Statistics, University of Glasgow, Glasgow, United Kingdom

ORICD: https://orcid.org/0000-0003-0805-0195

Thomas Williams

Roles: Conceptualization, Investigation, Methodology, Writing – review & editing

Affiliations: NHS Lothian, Edinburgh, United Kingdom, Royal Hospital for Children and Young People, University of Edinburgh, Edinburgh, United Kingdom

Emma C. Thomson

Roles: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing

E-mail: [email protected]

Affiliations: MRC–University of Glasgow Centre for Virus Research (CVR), Glasgow, United Kingdom, NHS Greater Glasgow and Clyde, Glasgow, United Kingdom, London School of Hygiene and Tropical Medicine, London, United Kingdom

ORICD: https://orcid.org/0000-0003-1482-0889

The COVID-19 Genomics UK (COG-UK) Consortium

¶Membership of the COVID-19 Genomics UK (COG-UK) Consortium is provided in the Acknowledgments section.

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