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Whole-genome sequencing (WGS) has been championed within the UK National Health Service (NHS) and represents one of the approaches within the forthcoming UK National Genomic Test Directory to identify genetic variants that cause particular rare inherited diseases.1 Although diploid organisms such as man develop from a single cell, postzygotic somatic mutations occur and lead to mosaicism.2 Sufficiently early generation of a disease-causing DNA sequence variant can result in a mosaic individual who is the first member of a family to be affected by an inherited disorder.3 4 Their causative DNA sequence variant is likely to be present at less than the 50% expected for a heterozygote, and may be difficult to detect with confidence. Greater ability to detect mosaicism has been used to favour higher depth panel-based sequencing rather than WGS as, due to sequencing capacities, there are trade-offs between the number of target nucleotides sequenced and the average depth of reads at any given nucleotide. It is increasingly recognised that hereditary haemorrhagic telangiectasia (HHT5) is a condition where the first affected member of the family may be a mosaic.3 4 HHT is transmitted as an autosomal dominant trait via a single pathogenic DNA sequence variant, usually in ENG , ACVRL1 or SMAD4 .5 There are hundreds of different pathogenic variants in these genes in different HHT families, all resulting in similar clinical features.6 HHT is diagnosed clinically by the presence of at least three Curacao Criteria: recurrent nosebleeds, mucocutaneous telangiectasia, visceral involvement such as pulmonary, hepatic, gastrointestinal or cerebral arteriovenous malformations (AVMs), and an affected first-degree relative.5 A high index of suspicion for HHT is warranted, particularly in cases where more than one AVM is present or where multiple generations display these features. As we have shown, however, high proportions of …

The abnormal vascular structures of hereditary hemorrhagic telangiectasia (HHT) often cause severe anemia due to recurrent hemorrhage, but HHT causal genes do not predict the severity of hematological complications. We tested for chance inheritance and clinical associations of rare deleterious variants in which loss-of-function causes bleeding or hemolytic disorders in the general population. In double-blinded analyses, all 104 patients with HHT from a single reference center recruited to the 100 000 Genomes Project were categorized on new MALO (more/as-expected/less/opposite) sub-phenotype severity scales, and whole genome sequencing data were tested for high impact variants in 75 HHT-independent genes encoding coagulation factors, or platelet, hemoglobin, erythrocyte enzyme, and erythrocyte membrane constituents. Rare variants (all gnomAD allele frequencies 15 were supported by gene-level mutation significance cutoff scores. CADD >15 variants were identified in 38/104 (36.5%) patients with HHT, found for 1 in 10 patients within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to HHT vessels had more CADD-deleterious variants in platelet (Spearman ρ = 0.25; P = .008) and coagulation (Spearman ρ = 0.21; P = .024) genes. However, the HHT cohort had 60% fewer deleterious variants in platelet and coagulation genes than expected (Mann-Whitney test P = .021). In conclusion, patients with HHT commonly have rare variants in genes of relevance to their phenotype, offering new therapeutic targets and opportunities for informed, personalized medicine strategies.

Possession of a clinical or molecular disease label alters the context in which life-course events operate, but rarely explains the phenotypic variability observed by clinicians. Whole genome sequencing of unselected endothelial vasculopathy patients demonstrated more than a third had rare, likely deleterious variants in clinically-relevant genes unrelated to their vasculopathy (1 in 10 within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes). High erythrocyte membrane variant rates paralleled genomic damage and prevalence indices in the general population. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to their vasculopathy had more deleterious variants in platelet (Spearman ρ=0.25, p=0.008) and coagulation (Spearman ρ=0.21, p=0.024) genes. We conclude that rare diseases can provide insights for medicine beyond their primary pathophysiology, and propose a framework based on rare variants to inform interpretative approaches to accelerate clinical impact from whole genome sequencing.

Background: On March 11, 2020 the World Health Organisation declared the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing Coronavirus Disease 2019 (COVID-19) syndrome, as a pandemic. The UK mass vaccination programme commenced on December 08, 2020 vaccinating groups of the population deemed to be most vulnerable to severe COVID-19 infection. Objective: To assess the early vaccine administration coverage and outcome data across an integrated care system in North West London (NWL), leveraging a unique population-level care dataset. Vaccine effectiveness of a single dose of the Oxford/Astrazeneca and Pfizer/BioNtech vaccines were compared. Methods: A retrospective cohort study identified 2,183,939 individuals eligible for COVID-19 vaccination between December 08, 2020 and February 24, 2021 within a primary, secondary and community care integrated care dataset. These data were used to assess vaccination hesitancy across ethnicity, gender and socio-economic deprivation measures (Pearson Product-Moment Correlations); investigated COVID-19 transmission related to vaccination hubs; and assessed the early effectiveness of COVID-19 vaccination (after a single dose) using time to event analyses with multivariable Cox regression analysis to investigate if vaccination independently predicted positive SARS-CoV-2 in those vaccinated compared to those unvaccinated. Results: In the study 5.88% (24,332/413,919) of individuals declined and did not receive a vaccination. Black or Black British individuals had the highest rate of declining a vaccine at 16.14% (4,337/26,870). There was a strong negative association between socio-economic deprivation and rate of declining vaccination (r=-0.94, P=.002) with 13.5% (1980/14571) of individuals declining vaccination in the most deprived areas compared to 0.98% (869/9609) in the least. In the first six days after vaccination 344 of 389587 individuals tested positive for SARS-CoV-2 (0.09%). The rate increased to 0.13% (525/389,243) between days 7 and 13, before then gradually falling week on week. At 28 days post vaccination there was a 74% (HR 0.26 (0.19-0.35)) and 78% (HR 0.22 (0.18-0.27)) reduction in risk of testing positive for SARS-CoV-2 for individuals that received the Oxford/Astrazeneca and Pfizer/BioNTech vaccines respectively, when compared with unvaccinated individuals. A very low proportion of hospital admissions were seen in vaccinated individuals who tested positive for SARS-CoV-2 (0.01% of all patients vaccinated) providing evidence for vaccination effectiveness, after a single dose. Conclusions: There was no definitive evidence to suggest COVID-19 was transmitted as a result of vaccination hubs during the vaccine administration roll-out in NWL, and the risk of contracting COVID-19 and/or becoming hospitalised after vaccination has been demonstrated to be very low in the vaccinated population. This study provides further evidence that a single dose of either the Pfizer/BioNTech vaccine or the Oxford/Astrazeneca vaccine is effective at reducing the risk of testing positive for COVID-19 up to 60 days across all age groups, ethnic groups, and risk categories in an urban UK population.

Background: Real world data supporting the effectiveness of the COVID-19 vaccination strategy in the UK population is needed to guide health policy. This real-word data-driven evidence study of the UK COVID-19 Vaccination Programme in the Northwest London (NWL) population used a unique dataset established as part of the Gold Command Covid-19 response in NWL (iCARE https://imperialbrc.nihr.ac.uk/facilities/icare/), which included the pre-established Whole System Integrated Care (WSIC) data collated for the purposes of population health in the sector. Objective: To assess the early vaccine administration coverage and vaccine effectiveness and outcome data across an integrated care system of eight CCGs leveraging a unique population-level care dataset Methods: Design - Retrospective cohort study. Setting - Individuals eligible for COVID 19 vaccination in North West London based on linked primary and secondary care data. Participants - 2,183,939 individuals eligible for COVID 19 vaccination Results: During the NWL vaccine programme study time period 5.88% of individuals declined and did not receive a vaccination. Black or black British individuals had the highest rate of declining a vaccine at 16.14% (4,337). There was a strong negative association between deprivation and rate of declining vaccination (r=-0.94, p

Objective To assess the early vaccine administration coverage and vaccine effectiveness and outcome data across an integrated care system of eight CCGs leveraging a unique population-level care dataset Design Retrospective cohort study. Setting Individuals eligible for COVID 19 vaccination in North West London based on linked primary and secondary care data. Participants 2,183,939 individuals eligible for COVID 19 vaccination Results During the NWL vaccine programme study time period 5.88% of individuals declined and did not receive a vaccination. Black or black British individuals had the highest rate of declining a vaccine at 16.14% (4,337). There was a strong negative association between deprivation and rate of declining vaccination (r=-0.94, p

The health care system in England has been highly affected by the surge in demand due to patients afflicted by COVID-19. Yet the impact of the pandemic on the care seeking behaviour of patients and thus on Emergency department (ED) services is unknown, especially for non-COVID-19 related emergencies. In this report, we aimed to assess how the reorganisation of hospital care and admission policies to respond to the COVID-19 epidemic affected ED attendances and emergency hospital admissions. We performed time-series analyses of present year vs historic (2015-2019) trends of ED attendances between March 12 and May 31 at two large central London hospitals part of Imperial College Healthcare NHS Trust (ICHNT) and compared these to regional and national trends. Historic attendances data to ICHNT and publicly available NHS situation reports were used to calibrate time series auto-regressive integrated moving average (ARIMA) forecasting models. We thus predicted the (conterfactual) expected number of ED attendances between March 12 (when the first public health measure leading to lock-down started in England) to May 31, 2020 (when the analysis was censored) at ICHNT, at all acute London Trusts and nationally. The forecasted trends were compared to observed data for the same periods of time. Lastly, we analysed the trends at ICHNT disaggregating by mode of arrival, distance from postcode of patient residence to hospital and primary diagnosis amongst those that were subsequently admitted to hospital and compared these data to an average for the same period of time in the years 2015 to 2019. During the study period (January 1 to May 31, 2020) there was an overall decrease in ED attendances of 35% at ICHNT, of 50% across all London NHS Trusts and 53% nationally. For ICHNT, the decrease in attendances was mainly amongst those aged younger than 65 and those arriving by their own means (e.g. personal or public transport). Increasing distance (km) from postcode of residence to hospital was a significant predictor of reduced attendances, which could not be explained by weighted (for population numbers) mean index of multiple deprivation. Non-COVID emergency admissions to hospital after March 12 fell by 48% at ICHNT compared to previous years. This was seen across all disease areas, including acute coronary syndromes, stroke and cancer-related emergencies. The overall non-COVID-19 hospitalisation mortality risk did not differ (RR 1.13, 95%CI 0.94-1.37, p=0.19), also in comparison to previous years. Our findings suggest emergency healthcare seeking to hospitals drastically changed amongst the population within the catchment area of ICHNT. This trend was echoed regionally and nationally, suggesting those suffering a medical emergency may not have attended other (i.e. closer-to-home) hospitals. Furthermore, our time-series analyses showed that, even after COVID-19 cases and deaths decreased (i.e. from early April), non-COVID-19 ED attendances did not increase. The impact of emergency triaging systems (e.g. 111 calls) and alternative (e.g. private hospital, chemist) health services on these trends remains unknown. However, another recent report found increased non-COVID excess deaths in the community, which may be partially explained by people experiencing an emergency and not attending health services at all. Whether those that attended ED services have done so with longer delays from the moment of emergency onset also remains unknown. National analyses into the factors causing reduced attendances to ED services and strategies to revert these negative trends are urgently needed.

The Nigerian Field, 57 (3-4), 113-118