Investigating the presence and impact of competing events on prognostic model research

Prognostic models are used to predict an individual’s future health outcomes, including the risk of disease progression and the development of further complications. The statistical methodology used to develop these models is often naïve to the presence of competing events, these are events which prevent or alter the probability of an outcome of interest from occurring. Not appropriately accounting for competing events is known to produce inflated absolute risk predictions for time-to-event outcomes, this bias is known as competing risks bias. However, there has been relatively little research about competing events in prognostic model research, for which absolute risk predictions are a key outcome. This thesis investigates the presence and impact of competing events on prognostic model research. To begin, two reviews were conducted to determine the presence, reporting, and management of competing events in current prediction model literature. Then competing risks statistical regression methods were applied to develop and internally validate a prognostic model using existing study data. These models were compared to models developed using standard time-to-event analysis techniques, naïve to competing events, with an external validation study. Finally, a simulation study was performed to identify the circumstances for which competing risks bias affects the predictive ability and calibration of prognostic models, with an overall aim to provide guidance for the optimal approaches to incorporate competing risks in prognostic model research

Investigating the impact of financial concerns on symptoms of depression in UK healthcare workers: data from the UK-REACH nationwide cohort study

BACKGROUND: Exploration of the association between financial concerns and depression in UK healthcare workers (HCWs) is paramount given the current 'cost of living crisis', ongoing strike action and recruitment/retention problems in the National Health Service. AIMS: To assess the impact of financial concerns on the risk of depression in HCWs, how these concerns have changed over time and what factors might predict financial concerns. METHOD: We used longitudinal survey data from a UK-wide cohort of HCWs to determine whether financial concerns at baseline (December 2020 to March 2021) were associated with depression (measured with the Public Health Questionnaire-2) at follow-up (June to October 2022). We used logistic regression to examine the association between financial concerns and depression, and ordinal logistic regression to establish predictors of developing financial concerns. RESULTS: A total of 3521 HCWs were included. Those concerned about their financial situation at baseline had higher odds of developing depressive symptoms at follow-up. Financial concerns increased in 43.8% of HCWs and decreased in 9%. Those in nursing, midwifery and other nursing roles had over twice the odds of developing financial concerns compared with those in medical roles. CONCLUSIONS: Financial concerns are increasing in prevalence and predict the later development of depressive symptoms in UK HCWs. Those in nursing, midwifery and other allied nursing roles may have been disproportionately affected. Our results are concerning given the potential effects on sickness absence and staff retention. Policy makers should act to alleviate financial concerns to reduce the impact this may have on a discontent workforce plagued by understaffing

Impact of chronic kidney disease on case ascertainment for hospitalised acute myocardial infarction: an English cohort study.

OBJECTIVES: Acute myocardial infarction (AMI) case ascertainment improves for the UK general population using linked health data sets. Because care pathways for people with chronic kidney disease (CKD) change based on disease severity, AMI case ascertainment for these people may differ compared with the general population. We aimed to determine the association between CKD severity and AMI case ascertainment in two secondary care data sets, and the agreement in estimated glomerular filtration rate (eGFR) between the same data sets. METHODS: We used a cohort study design. Primary care records for people with CKD or risk factors for CKD, identified using the National CKD Audit (2015-2017), were linked to the Myocardial Ischaemia National Audit Project (MINAP, 2007-2017) and Hospital Episode Statistics (HES, 2007-2017) secondary care registries. People with an AMI recorded in either MINAP, HES or both were included in the study cohort. CKD status was defined using eGFR, derived from the most recent serum creatinine value recorded in primary care. Moderate-severe CKD was defined as eGFR <60 mL/min/1.73 m2, and mild CKD or at risk of CKD was defined as eGFR ≥60 mL/min/1.73 m2 or eGFR missing. CKD stages were grouped as (1) At risk of CKD and Stages 1-2 (eGFR missing or ≥60 mL/min/1.73 m2), (2) Stage 3a (eGFR 45-59 mL/min/1.73 m2), (3) Stage 3b (eGFR 30-44 mL/min/1.73 m2) and (4) Stages 4-5 (eGFR <30 mL/min/1.73 m2). RESULTS: We identified 6748 AMIs: 23% were recorded in both MINAP and HES, 66% in HES only and 11% in MINAP only. Compared with people at risk of CKD or with mild CKD, AMIs in people with moderate-severe CKD were more likely to be recorded in both MINAP and HES (42% vs 11%, respectively), or MINAP only (22% vs 5%), and less likely to be recorded in HES only (36% vs 84%). People with AMIs recorded in HES only or MINAP only had increased odds of death during hospitalisation compared with those recorded in both (adjusted OR 1.61, 95% CI 1.32 to 1.96 and OR 1.60, 95% CI 1.26 to 2.04, respectively). Agreement between eGFR at AMI admission (MINAP) and in primary care was poor (kappa (K) 0.42, SE 0.012). CONCLUSIONS: AMI case ascertainment is incomplete in both MINAP and HES, and is associated with CKD severity

Investigating the impact of financial concerns on symptoms of depression in UK healthcare workers: data from the UK-REACH nationwide cohort study

Background Exploration of the association between financial concerns and depression in UK healthcare workers (HCWs) is paramount given the current ‘cost of living crisis’, ongoing strike action and recruitment/retention problems in the National Health Service. Aims To assess the impact of financial concerns on the risk of depression in HCWs, how these concerns have changed over time and what factors might predict financial concerns. Method We used longitudinal survey data from a UK-wide cohort of HCWs to determine whether financial concerns at baseline (December 2020 to March 2021) were associated with depression (measured with the Public Health Questionnaire-2) at follow-up (June to October 2022). We used logistic regression to examine the association between financial concerns and depression, and ordinal logistic regression to establish predictors of developing financial concerns. Results A total of 3521 HCWs were included. Those concerned about their financial situation at baseline had higher odds of developing depressive symptoms at follow-up. Financial concerns increased in 43.8% of HCWs and decreased in 9%. Those in nursing, midwifery and other nursing roles had over twice the odds of developing financial concerns compared with those in medical roles. Conclusions Financial concerns are increasing in prevalence and predict the later development of depressive symptoms in UK HCWs. Those in nursing, midwifery and other allied nursing roles may have been disproportionately affected. Our results are concerning given the potential effects on sickness absence and staff retention. Policy makers should act to alleviate financial concerns to reduce the impact this may have on a discontent workforce plagued by understaffing

United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers (UK-REACH): a retrospective cohort study using linked routinely collected data, study protocol

Introduction: COVID-19 has spread rapidly worldwide, causing significant morbidity and mortality. People from ethnic minorities, particularly those working in healthcare settings, have been disproportionately affected. Current evidence of the association between ethnicity and COVID-19 outcomes in people working in healthcare settings is insufficient to inform plans to address health inequalities. Methods and analysis: This study combines anonymised human resource databases with professional registration and National Health Service data sets to assess associations between ethnicity and COVID-19 diagnosis, hospitalisation and death in healthcare workers in the UK. Adverse COVID-19 outcomes will be assessed between 1 February 2020 (date following first confirmed COVID-19 case in UK) and study end date (31 January 2021), allowing 1-year of follow-up. Planned analyses include multivariable Poisson, logistic and flexible parametric time-to-event regression within each country, adjusting for core predictors, followed by meta-analysis of country-specific results to produce combined effect estimates for the UK. Mediation analysis methods will be explored to examine the direct, indirect and mediated interactive effects between ethnicity, occupational group and COVID-19 outcomes. Ethics and dissemination: Ethical approval for the UK-REACH programme has been obtained via the expedited HRA COVID-19 processes (REC ref: 20/HRA/4718, IRAS ID: 288316). Research information will be anonymised via the Secure Anonymised Information Linkage Databank before release to researchers. Study results will be submitted for publication in an open access peer-reviewed journal and made available on our dedicated website (https://uk-reach.org/). Trial registration number: ISRCTN11811602

Impact of vaccination on the association of COVID-19 with cardiovascular diseases: An OpenSAFELY cohort study

Infection with SARS-CoV-2 is associated with an increased risk of arterial and venous thrombotic events, but the implications of vaccination for this increased risk are uncertain. With the approval of NHS England, we quantified associations between COVID-19 diagnosis and cardiovascular diseases in different vaccination and variant eras using linked electronic health records for ~40% of the English population. We defined a ‘pre-vaccination’ cohort (18,210,937 people) in the wild-type/Alpha variant eras (January 2020-June 2021), and ‘vaccinated’ and ‘unvaccinated’ cohorts (13,572,399 and 3,161,485 people respectively) in the Delta variant era (June-December 2021). We showed that the incidence of each arterial thrombotic, venous thrombotic and other cardiovascular outcomes was substantially elevated during weeks 1-4 after COVID-19, compared with before or without COVID-19, but less markedly elevated in time periods beyond week 4. Hazard ratios were higher after hospitalised than non-hospitalised COVID-19 and higher in the pre-vaccination and unvaccinated cohorts than the vaccinated cohort. COVID-19 vaccination reduces the risk of cardiovascular events after COVID-19 infection. People who had COVID-19 before or without being vaccinated are at higher risk of cardiovascular events for at least two years

Case-ascertainment of acute myocardial infarction hospitalizations in cancer patients: a cohort study using English linked electronic health data.

AIMS: To assess the recording and accuracy of acute myocardial infarction (AMI) hospital admissions between two electronic health record databases within an English cancer population over time and understand the factors that affect case-ascertainment. METHODS AND RESULTS: We identified 112 502 hospital admissions for AMI in England 2010-2017 from the Myocardial Ischaemia National Audit Project (MINAP) disease registry and hospital episode statistics (HES) for 95 509 patients with a previous cancer diagnosis up to 15 years prior to admission. Cancer diagnoses were identified from the National Cancer Registration Dataset (NCRD). We calculated the percentage of AMI admissions captured by each source and examined patient characteristics associated with source of ascertainment. Survival analysis assessed whether differences in survival between case-ascertainment sources could be explained by patient characteristics. A total of 57 265 (50.9%) AMI admissions in patients with a prior diagnosis of cancer were captured in both MINAP and HES. Patients captured in both sources were younger, more likely to have ST-segment elevation myocardial infarction and had better prognosis, with lower mortality rates up to 9 years after AMI admission compared with patients captured in only one source. The percentage of admissions captured in both data sources improved over time. Cancer characteristics (site, stage, and grade) had little effect on how AMI was captured. CONCLUSION: MINAP and HES define different populations of patients with AMI. However, cancer characteristics do not substantially impact on case-ascertainment. These findings support a strategy of using multiple linked data sources for observational cardio-oncological research into AMI

Impact of vaccination on the association of COVID-19 with cardiovascular diseases:An OpenSAFELY cohort study

Infection with SARS-CoV-2 is associated with an increased risk of arterial and venous thrombotic events, but the implications of vaccination for this increased risk are uncertain. With the approval of NHS England, we quantified associations between COVID-19 diagnosis and cardiovascular diseases in different vaccination and variant eras using linked electronic health records for ~40% of the English population. We defined a 'pre-vaccination' cohort (18,210,937 people) in the wild-type/Alpha variant eras (January 2020-June 2021), and 'vaccinated' and 'unvaccinated' cohorts (13,572,399 and 3,161,485 people respectively) in the Delta variant era (June-December 2021). We showed that the incidence of each arterial thrombotic, venous thrombotic and other cardiovascular outcomes was substantially elevated during weeks 1-4 after COVID-19, compared with before or without COVID-19, but less markedly elevated in time periods beyond week 4. Hazard ratios were higher after hospitalised than non-hospitalised COVID-19 and higher in the pre-vaccination and unvaccinated cohorts than the vaccinated cohort. COVID-19 vaccination reduces the risk of cardiovascular events after COVID-19 infection. People who had COVID-19 before or without being vaccinated are at higher risk of cardiovascular events for at least two years.</p

Validation and Recalibration of Two Multivariable Prognostic Models for Survival and Independence in Acute Stroke

Introduction Various prognostic models have been developed for acute stroke, including one based on age and five binary variables (‘six simple variables’ model; SSVMod) and one based on age plus scores on the National Institutes of Health Stroke Scale (NIHSSMod). The aims of this study were to externally validate and recalibrate these models, and to compare their predictive ability in relation to both survival and independence. Methods Data from a large clinical trial of oxygen therapy (n = 8003) were used to determine the discrimination and calibration of the models, using C-statistics, calibration plots, and Hosmer-Lemeshow statistics. Methods of recalibration in the large and logistic recalibration were used to update the models. Results For discrimination, both models functioned better for survival (C-statistics between .802 and .837) than for independence (C-statistics between .725 and .735). Both models showed slight shortcomings with regard to calibration, over-predicting survival and under-predicting independence; the NIHSSMod performed slightly better than the SSVMod. For the most part, there were only minor differences between ischaemic and haemorrhagic strokes. Logistic recalibration successfully updated the models for a clinical trial population. Conclusions Both prognostic models performed well overall in a clinical trial population. The choice between them is probably better based on clinical and practical considerations than on statistical considerations

Ethnic differences in cellular and humoral immune responses to SARS-CoV-2 vaccination in UK healthcare workers: a cross-sectional analysis

Background: Few studies have compared SARS-CoV-2 vaccine immunogenicity by ethnic group. We sought to establish whether cellular and humoral immune responses to SARS-CoV-2 vaccination differ according to ethnicity in UK Healthcare workers (HCWs). Methods: In this cross-sectional analysis, we used baseline data from two immunological cohort studies conducted in HCWs in Leicester, UK. Blood samples were collected between March 3, and September 16, 2021. We excluded HCW who had not received two doses of SARS-CoV-2 vaccine at the time of sampling and those who had serological evidence of previous SARS-CoV-2 infection. Outcome measures were SARS-CoV-2 spike-specific total antibody titre, neutralising antibody titre and ELISpot count. We compared our outcome measures by ethnic group using univariable (t tests and rank-sum tests depending on distribution) and multivariable (linear regression for antibody titres and negative binomial regression for ELISpot counts) tests. Multivariable analyses were adjusted for age, sex, vaccine type, length of interval between vaccine doses and time between vaccine administration and sample collection and expressed as adjusted geometric mean ratios (aGMRs) or adjusted incidence rate ratios (aIRRs). To assess differences in the early immune response to vaccination we also conducted analyses in a subcohort who provided samples between 14 and 50 days after their second dose of vaccine. Findings: The total number of HCWs in each analysis were 401 for anti-spike antibody titres, 345 for neutralising antibody titres and 191 for ELISpot. Overall, 25.4% (19.7% South Asian and 5.7% Black/Mixed/Other) were from ethnic minority groups. In analyses including the whole cohort, neutralising antibody titres were higher in South Asian HCWs than White HCWs (aGMR 1.47, 95% CI [1.06–2.06], P = 0.02) as were T cell responses to SARS-CoV-2 S1 peptides (aIRR 1.75, 95% CI [1.05–2.89], P = 0.03). In a subcohort sampled between 14 and 50 days after second vaccine dose, SARS-CoV-2 spike-specific antibody and neutralising antibody geometric mean titre (GMT) was higher in South Asian HCWs compared to White HCWs (9616 binding antibody units (BAU)/ml, 95% CI [7178–12,852] vs 5888 BAU/ml [5023–6902], P = 0.008 and 2851 95% CI [1811–4487] vs 1199 [984–1462], P &lt; 0.001 respectively), increments which persisted after adjustment (aGMR 1.26, 95% CI [1.01–1.58], P = 0.04 and aGMR 2.01, 95% CI [1.34–3.01], P = 0.001). SARS-CoV-2 ELISpot responses to S1 and whole spike peptides (S1 + S2 response) were higher in HCWs from South Asian ethnic groups than those from White groups (S1: aIRR 2.33, 95% CI [1.09–4.94], P = 0.03; spike: aIRR, 2.04, 95% CI [1.02–4.08]). Interpretation: This study provides evidence that, in an infection naïve cohort, humoral and cellular immune responses to SARS-CoV-2 vaccination are stronger in South Asian HCWs than White HCWs. These differences are most clearly seen in the early period following vaccination. Further research is required to understand the underlying mechanisms, whether differences persist with further exposure to vaccine or virus, and the potential impact on vaccine effectiveness. Funding: DIRECT and BELIEVE have received funding from UK Research and Innovation (UKRI) through the COVID-19 National Core Studies Immunity (NCSi) programme (MC_PC_20060)