Gene-Environment Interaction Analysis Incorporating Sex, Cardiometabolic Diseases, and Multiple Deprivation Index Reveals Novel Genetic Associations With COVID-19 Severity

Increasing evidence indicates that specific genetic variants influence the severity of outcomes after infection with COVID-19. However, it is not clear whether the effect of these genetic factors is independent of the risk due to more established non-genetic demographic and metabolic risk factors such as male sex, poor cardiometabolic health, and low socioeconomic status. We sought to identify interactions between genetic variants and non-genetic risk factors influencing COVID-19 severity via a genome-wide interaction study in the UK Biobank. Of 378,051 unrelated individuals of European ancestry, 2,402 were classified as having experienced severe COVID-19, defined as hospitalization or death due to COVID-19. Exposures included sex, cardiometabolic risk factors [obesity and type 2 diabetes (T2D), tested jointly], and multiple deprivation index. Multiplicative interaction was tested using a logistic regression model, conducting both an interaction test and a joint test of genetic main and interaction effects. Five independent variants reached genome-wide significance in the joint test, one of which also reached significance in the interaction test. One of these, rs2268616 in the placental growth factor (PGF) gene, showed stronger effects in males and in individuals with T2D. None of the five variants showed effects on a similarly-defined phenotype in a lookup in the COVID-19 Host Genetics Initiative. These results reveal potential additional genetic loci contributing to COVID-19 severity and demonstrate the value of including non-genetic risk factors in an interaction testing approach for genetic discovery.

Developing a fast-track COVID-19 vaccination clinic for pregnant people

A pilot fast-track COVID-19 vaccination clinic was created in the east of England to provide expert advice, education and support for pregnant people. As the COVID-19 pandemic has progressed, it is clear that pregnant people are at high risk of becoming seriously unwell with the COVID-19 virus. Establishment of the clinic led to a 20% increase in COVID-19 vaccine uptake in this group, with 211 vaccinations between 28 June and 30 September 2021. Almost two-thirds (59%) of pregnant people reported they would not have taken up the vaccination if they had not discussed it as part of this service. Over half of those attending (50.2%) reside within the index of multiple deprivation levels 1–4, the most severely deprived areas. This article explores the development of the fast-track vaccination service and seeks to support others wishing to replicate its delivery in their areas.

Comparative effectiveness of ChAdOx1 versus BNT162b2 vaccines against SARS-CoV-2 infections in England and Wales: A cohort analysis using trial emulation in the Virus Watch community data

Introduction: Infections of SARS-CoV-2 in vaccinated individuals have been increasing globally. Understanding the associations between vaccine type and a post-vaccination infection could help prevent further COVID-19 waves. In this paper, we use trial emulation to understand the impact of a phased introduction of the vaccine in the UK driven by vulnerability and exposure status. We estimate the comparative effectiveness of COVID-19 vaccines (ChAdOx1 versus BNT162b2) against post-vaccination infections of SARS-CoV-2 in a community setting in England and Wales. Method: Trial emulation was conducted by pooling results from six cohorts whose recruitment was staggered between 1st January 2021 and 31st March 2021 and followed until 12th November 2021. Eligibility for each trial was based upon age (18+ at the time of vaccination), without prior signs of infection or an infection within the first 14 days of the first dose. Time from vaccination of ChAdOx1 or BNT162b2 until SARS-CoV-2 infection (positive polymerase chain reaction or lateral flow test after 14 of the vaccination) was modelled using Cox proportional hazards model for each cohort and adjusted for age at vaccination, gender, minority ethnic status, clinically vulnerable status and index of multiple deprivation quintile. For those without SARS-CoV-2 infection during the study period, follow-up was until loss-of-follow-up or end of study (12th November 2021). Pooled hazard ratios were generated using random-effects meta-analysis. Results: Across six cohorts, there were a total of 21,283 participants who were eligible and vaccinated with either ChAdOx1 (n = 13,813) or BNT162b2 (n = 7,470) with a median follow-up time of 266 days (IQR: 235 - 282). By November 12th 2021, 750 (5.4%) adults who had ChAdOx1 as their vaccine experienced a SARS-CoV-2 infection, compared to 296 (4.0%) who had BNT162b2. We found that people who received ChAdOx1 vaccinations had 10.54 per 1000 people higher cumulative incidence for SARS-CoV-2 infection compared to BNT162b2 for infections during a maximum of 315 days of follow-up. When adjusted for age at vaccination, sex, minority ethnic status, index of multiple deprivation, and clinical vulnerability status, we found a pooled adjusted hazard ratio of 1.35 [HR: 1.35, 95%CI: 1.15 - 1.58], demonstrating a 35% increase in SARS-CoV-2 infections in people who received ChAdOx1 compared to BNT162b2. Discussion: We found evidence of greater effectiveness of receiving BNT162b2 compared to ChAdOx1 vaccines against SARS-CoV-2 infection in England and Wales during a time period when Delta became the most prevalent variant of concern. Our findings demonstrate the importance of booster (third) doses to maintain protection and suggest that these should be prioritised to those who received ChAdOx1 as their primary course.

Scottish Index of Multiple Deprivation (SIMD) Indicators as Predictors of Mortality Among Patients Hospitalised with COVID-19 Disease in the Lothian Region, Scotland During the First Wave: A Cohort Study

Background: Sars-CoV-2, the causative agent of COVID-19, has led to more than 100,000 deaths in the UK and multiple risk factors for mortality including age, sex and deprivation have been identified. This study aimed to identify which indicators of Scottish Index of Multiple Deprivation (SIMD), an area-based deprivation index, were predictive of mortality. Methods: This was a prospective cohort study of anonymised electronic health records of 710 consecutive patients hospitalised with Covid-19 disease between March and June 2020 in the Lothian Region of Southeast Scotland. Data sources included automatically extracted data from national electronic platforms and manually extracted data from individual admission records. Exposure variables of interest were SIMD quintiles and more specifically 12 indicators of deprivation deemed clinically relevant selected from the SIMD. Our primary outcome was mortality. Univariable and multivariable logistic regression analyses adjusted for age and sex were used to determine measures of association between exposures of interest and the primary outcome. Results: After adjusting for age and sex, we found an increased risk of mortality in the more deprived SIMD quintiles 1 and 3 (OR 1.75, CI 0.99-3.08, p=0.053 and OR 2.17, CI 1.22-3.86, p=0.009, respectively), but this association was not significant in our multivariable model adjusted for co-morbidities and clinical parameters of severity at admission. Of the 12 pre-selected indicators of deprivation, two were associated with greater mortality in our multivariable analysis: income deprivation rate categorised by quartile (Q4 (most deprived): 2.11 (1.20-3.77) p=0.011)) and greater than expected hospitalisations due to alcohol per SIMD data zone (1.96 (1.28-3.00) p=0.002)). Conclusions: In contrast to other studies, deprivation quintile distribution was not predictive of mortality in our cohort. This possibly reflects the greater affluence and ethnic homogeneity of the Lothian Region compared to the rest of Scotland. We identified an increased risk of mortality in patients residing in areas with greater income-deprivation and/or number of hospitalisations due to alcohol. In areas where aggregate measures fail to capture pockets of deprivation, specific indicators may be helpful in targeting resources to residents at risk of poorer outcomes from Covid-19.

Associations between dietary patterns and metabolic syndrome in older adults in New Zealand: the REACH study

Metabolic syndrome is common in older adults and may be modified by the diet. The aim of this study was to examine associations between a posteriori dietary patterns and metabolic syndrome in an older New Zealand population. The REACH study (Researching Eating, Activity, and Cognitive Health) included 366 participants (65-74 years, 36% male) living independently in Auckland, New Zealand. Dietary data were collected using a 109-item food frequency questionnaire with demonstrated validity and reproducibility for assessing dietary patterns using principal component analysis. Metabolic syndrome was defined by the National Cholesterol Education Program Adult Treatment Panel III. Associations between dietary patterns and metabolic syndrome, adjusted for age, sex, index of multiple deprivation, physical activity, and energy intake were analysed using logistic regression analysis. Three dietary patterns explained 18% of dietary intake variation – ‘Mediterranean style’ (salad/leafy cruciferous/other vegetables, avocados/olives, alliums, nuts/seeds, shellfish and white/oily fish, berries), ‘prudent’ (dried/fresh/frozen legumes, soy-based foods, whole grains, carrots), and ‘Western’ (processed meat/fish, sauces/condiments, cakes/biscuits/puddings, meat pies/hot chips). No associations were seen between ‘Mediterranean style’ [OR=0.75 (95% CI 0.53, 1.06), P=0.11] or ‘prudent’ [OR=1.17 (95% CI 0.83, 1.59), P=0.35] patterns and metabolic syndrome after co-variate adjustment. The ‘Western’ pattern was positively associated with metabolic syndrome [OR=1.67 (95% CI 1.08, 2.63), P=0.02]. There was also a small association between an index of multiple deprivation [OR=1.04 (95% CI 1.02, 1.06), P<0.001] and metabolic syndrome. This cross-sectional study provides further support for a Western dietary pattern being a risk factor for metabolic syndrome in an older population.

Inequalities in population health loss by multiple deprivation: COVID-19 and pre-pandemic all-cause disability-adjusted life years (DALYs) in Scotland

Background COVID-19 has caused almost unprecedented change across health, education, the economy and social interaction. It is widely understood that the existing mechanisms which shape health inequalities have resulted in COVID-19 outcomes following this same, familiar, pattern. Our aim was to estimate inequalities in the population health impact of COVID-19 in Scotland, measured by disability-adjusted life years (DALYs) in 2020. Our secondary aim was to scale overall, and inequalities in, COVID-19 DALYs against the level of pre-pandemic inequalities in all-cause DALYs, derived from the Scottish Burden of Disease (SBoD) study. Methods National deaths and daily case data were input into the European Burden of Disease Network consensus model to estimate DALYs. Total Years of Life Lost (YLL) were estimated for each area-based deprivation quintile of the Scottish population. Years Lived with Disability were proportionately distributed to deprivation quintiles, based on YLL estimates. Inequalities were measured by: the range, Relative Index of Inequality (RII), Slope Index of Inequality (SII), and attributable DALYs were estimated by using the least deprived quintile as a reference. Results Marked inequalities were observed across several measures. The SII range was 2048 to 2289 COVID-19 DALYs per 100,000 population. The rate in the most deprived areas was around 58% higher than the mean population rate (RII = 1.16), with 40% of COVID-19 DALYs attributed to differences in area-based deprivation. Overall DALYs due to COVID-19 ranged from 7 to 20% of the annual pre-pandemic impact of inequalities in health loss combined across all causes. Conclusion The substantial population health impact of COVID-19 in Scotland was not shared equally across areas experiencing different levels of deprivation. The extent of inequality due to COVID-19 was similar to averting all annual DALYs due to diabetes. In the wider context of population health loss, overall ill-health and mortality due to COVID-19 was, at most, a fifth of the annual population health loss due to inequalities in multiple deprivation. Implementing effective policy interventions to reduce health inequalities must be at the forefront of plans to recover and improve population health.

Regionale Deprivation und Merkmale der Krankheit und ihrer Versorgung bei chronisch-entzündlichen Darmerkrankungen

Zusammenfassung Hintergrund Regionale Deprivation ist als ökologischer Parameter eine Komponente der sozialen Determinanten von Gesundheit. Zu ihrer Messung stehen in Deutschland der „German Index of Multiple Deprivation“ (GIMD) und der „German Index of Socioeconomic Deprivation“ (GISD) zur Verfügung. Chronisch entzündliche Darmerkrankungen (CED) sind keine häufigen, aber ernste körperliche Erkrankungen unklarer Ätiologie, mit vergleichsweise frühem Auftreten im Erwachsenenalter, oft chronisch-behandlungsbedürftigem Verlauf und unsicherer Prognose. Daten einer kontrollierten Versorgungsstudie erlauben es, Assoziationen zwischen regio-naler Deprivation und Merkmalen der Krankheit und ihrer Versorgung zu untersuchen. Wir erwarteten ungünstigere Krankheitsverhältnisse bei höherer Deprivation. Methodik Vorgestellt werden deskriptive Zusatzauswertungen (n=530) der 2016 bis 2019 durchgeführten MERCED-Studie zu Wirksamkeit und Nutzen einer stationären medizinischen Rehabilitation bei Sozialversicherten mit einer CED. Analysiert wurden Daten aus der Basisbefragung zu selbstberichteten Krankheitsmerkmalen, Krankheitsfolgen und Versorgungsleistungen in ihrem Zusammenhang mit dem Ausmaß regionaler Deprivation der Wohnregion (Kreisebene). Ergebnisse Die Zuordnung der Wohnregion der Kranken zu den Quintilen von GIMD und GISD korrelieren unter rho=0,76 miteinander (gewichtetes kappa=0,74). Regionale Deprivation zeigt, gemessen mit dem GIMD, überzufällige Unterschiede allein in den sozialen Teilhabeeinschränkungen (IMET) und der Zahl der „Einschränkungstage“. Dabei schildern sich Personen aus dem niedrigsten Deprivationsquintil als am stärksten eingeschränkt. Für die Einschränkungstage findet sich ein irre-guläres Muster. Beim GISD wird eine unsystematische Variation der gesundheitsbezogenen Lebensqualität (EQ-VAS) statistisch auffällig. Auch hier berichten Personen mit der geringsten regionalen Deprivation von einer besonders schlechten Lebensqualität. In einem Extremgruppenvergleich weisen Personen, die in nach GIMD und GISD stark deprivierten Regionen leben, günstigere Werte im Krankheitsverlauf beim IMET und EQ-VAS auf. Auch für Parameter der medizinischen Versorgung lassen sich keine systematischen Zusammenhänge mit den Deprivationsindizes darstellen. Schlussfolgerung Krankheitsmerkmale, Krankheitsfolgen und die medizinische Versorgung von CED-Kranken zeigen sich weitgehend unabhängig vom Ausmaß der mit zwei Indizes bestimmten regionalen Deprivation. Die wenigen auffälligen Unterschiede weisen in eine überraschende Richtung: Personen aus deprivierten Regionen berichten günstigere Krankheitsverhältnisse.

1404 NELA Risk Mortality Scores from Admission to Theatre in Emergency Gastrointestinal Perforation – A Retrospective Cohort Study

Background Patients with acute abdominal pathology requiring emergency laparotomy who experience a delay to theatre have an increased risk of morbidity, mortality and complications. The aim of this study was to assess delay, from symptom onset to theatre in patients with gastrointestinal perforation and its effect on perioperative risk. Method A single-centre retrospective study was performed in the Leeds Trust Hospitals, UK investigating the NELA database for patients requiring emergency laparotomy for perforated gastrointestinal viscus who presented to the acute surgical unit or emergency department between 1st February 2018 and 31st January 2020. Results 101 patients met the inclusion criteria (47% F and 53% M), mean age 59 [21-91]. 37% of patients’ NELA scores worsened from admission to pre-op (median change of + 5.9% IQR 1.3-11.5]), 14% stayed the same and 49% improved (median change of -4.4%[IQR 0.4-9.1]) 3% had their NELA score documented at the time of consent. 18% did not wait for a CT report or went straight to theatre. Mean time from admission to scan report was 9.3 hours (0.9-22.0). Median time from symptom onset to presentation (2 days [IQR 1-13]) was greater in patients with an Index of Multiple Deprivation Decile of 1-5, (n = 64, median 2 days [IQR 1-6]) compared to those in deciles 6-10, (n = 37, median 1 day[IQR 1-3]), p = 0.097. Conclusions NELA mortality risk score changes from presentation to surgery in patients with acute gastrointestinal perforation requiring emergency laparotomy. There is suggestion that delay in symptom onset to presentation may correlate with Index of Multiple Deprivation Decile.

Gene-environment interaction analysis incorporating sex, cardiometabolic diseases, and multiple deprivation index reveals novel genetic associations with COVID-19 severity

Increasing evidence indicates that specific genetic variants influence the severity of outcomes after infection with COVID-19. However, it is not clear whether the effect of these genetic factors is independent of the risk due to more established non-genetic demographic and metabolic risk factors such as male sex, poor cardiometabolic health, and low socioeconomic status. We sought to identify interactions between genetic variants and non-genetic risk factors influencing COVID-19 severity via a genome-wide interaction study in the UK Biobank. Of 378,051 unrelated individuals of European ancestry, 2,402 were classified as having experienced severe COVID-19, defined as hospitalization or death due to COVID-19. Exposures included sex, cardiometabolic risk factors (obesity and type 2 diabetes [T2D], tested jointly), and multiple deprivation index. Multiplicative interaction was tested using a logistic regression model, conducting both an interaction test and a joint test of genetic main and interaction effects. Five independent variants reached genome-wide significance in the joint test, one of which also reached significance in the interaction test. One of these, rs2268616 in the PGF gene, showed stronger effects in males and in individuals with T2D. None of the five variants showed effects on a similarly-defined phenotype in a lookup in the COVID-19 Host Genetics Initiative. These results reveal potential additional genetic loci contributing to COVID-19 severity and demonstrate the value of including non-genetic risk factors in an interaction testing approach for genetic discovery.