Core Concepts in Pharmacoepidemiology: Quantitative Bias Analysis.

Pharmacoepidemiological studies provide important information on the safety and effectiveness of medications, but the validity of study findings can be threatened by residual bias. Ideally, biases would be minimized through appropriate study design and statistical analysis methods. However, residual biases can remain, for example, due to unmeasured confounders, measurement error, or selection into the study. A group of sensitivity analysis methods, termed quantitative bias analyses, are available to assess, quantitatively and transparently, the robustness of study results to these residual biases. These approaches include methods to quantify how the estimated effect would be altered under specified assumptions about the potential bias, and methods to calculate bounds on effect estimates. This article introduces quantitative bias analyses for unmeasured confounding, misclassification, and selection bias, with a focus on their relevance and application to pharmacoepidemiological studies.

Use of non-steroidal anti-inflammatory drugs and risk of death from COVID-19: an OpenSAFELY cohort analysis based on two cohorts.

OBJECTIVES: To assess the association between routinely prescribed non-steroidal anti-inflammatory drugs (NSAIDs) and deaths from COVID-19 using OpenSAFELY, a secure analytical platform. METHODS: We conducted two cohort studies from 1 March to 14 June 2020. Working on behalf of National Health Service England, we used routine clinical data in England linked to death data. In study 1, we identified people with an NSAID prescription in the last 3 years from the general population. In study 2, we identified people with rheumatoid arthritis/osteoarthritis. We defined exposure as current NSAID prescription within the 4 months before 1 March 2020. We used Cox regression to estimate HRs for COVID-19 related death in people currently prescribed NSAIDs, compared with those not currently prescribed NSAIDs, accounting for age, sex, comorbidities, other medications and geographical region. RESULTS: In study 1, we included 536 423 current NSAID users and 1 927 284 non-users in the general population. We observed no evidence of difference in risk of COVID-19 related death associated with current use (HR 0.96, 95% CI 0.80 to 1.14) in the multivariable-adjusted model. In study 2, we included 1 708 781 people with rheumatoid arthritis/osteoarthritis, of whom 175 495 (10%) were current NSAID users. In the multivariable-adjusted model, we observed a lower risk of COVID-19 related death (HR 0.78, 95% CI 0.64 to 0.94) associated with current use of NSAID versus non-use. CONCLUSIONS: We found no evidence of a harmful effect of routinely prescribed NSAIDs on COVID-19 related deaths. Risks of COVID-19 do not need to influence decisions about the routine therapeutic use of NSAIDs.

Proton pump inhibitors and risk of all-cause and cause-specific mortality: A cohort study.

AIM: To investigate the association between proton pump inhibitors (PPIs) and both all-cause and cause-specific mortality. METHODS: We conducted a cohort study using the UK Clinical Practice Research Datalink GOLD database. We compared 733 885 new users of PPIs to 124 410 new users of H2 receptor antagonists (H2Ras). In a secondary analysis we compared 689 602 PPI new users to 1 361 245 nonusers of acid suppression therapy matched on age, sex and calendar year. Hazard ratios for all-cause and cause-specific mortality were estimated using propensity score (PS) weighted Cox models. RESULTS: PPI prescription was associated with increased risk of all-cause mortality, with hazard ratios decreasing considerably by increasing adjustment (unadjusted hazard ratio [HR] 1.65, 95% confidence interval [CI] 1.62-1.69; PS-weighted HR 1.38, 95% CI 1.33-1.44; high-dimensional PS-weighted HR 1.31, 95% CI 1.26-1.37). Short-term associations were observed with mortality from causes where a causal short-term association is unexpected (eg, lung cancer mortality: PS-weighted HR at 6 months 1.77, 95% CI 1.39-2.25). Adjusted hazard ratios were substantially higher when compared to nonusers (PS-weighted HR all-cause mortality 1.96, 95% CI 1.94-1.99) rather than H2RA users. CONCLUSIONS: PPI prescription was strongly associated with all-cause and cause-specific mortality. However, the change in hazard ratios (a) by increasing adjustment and (b) between comparator groups indicates that residual confounding is likely to explain the association between poor health outcomes and PPI use, and fully accounting for this using observational data may not be possible.

Measuring the Effectiveness of Real-World Evidence to Ensure Appropriate Impact.

The value of real-world evidence (RWE) in medicines regulation and health technology assessment has been increasingly emphasized. Nevertheless, although RWE is increasingly used, there has been limited systematic evidence of its value. A recent study that examined the role and impact of RWE in regulatory assessments conducted through the European Medicines Agency provided such evidence. Results of the study demonstrated RWE was important to decision making, particularly for certain questions such as the quantification of adverse events, the evaluation of risk minimization measures, and the assessment of product usage. The study suggested, however, that in many of the assessments further RWE would have been valuable and concluded that RWE has, as yet, played a limited role in hypothesis generation and in the assessment of medication effectiveness. This study had been possible only because of the transparency of the European Medicines Agency decision making. Ensuring transparency of RWE evidence collection, study design and conduct, and of decision making based on this evidence will facilitate further development of the uses and value of RWE. Keywords: benefit-risk assessment; medicines regulation; real-world evidence; regulatory decision making.

Whole-colon investigation vs. flexible sigmoidoscopy for suspected colorectal cancer based on presenting symptoms and signs: a multicentre cohort study.

BACKGROUND: Patients with suspected colorectal cancer (CRC) usually undergo colonoscopy. Flexible sigmoidoscopy (FS) may be preferred if proximal cancer risk is low. We investigated which patients could undergo FS alone. METHODS: Cohort study of 7375 patients (≥55 years) referred with suspected CRC to 21 English hospitals (2004-2007), followed using hospital records and cancer registries. We calculated yields and number of needed whole-colon examinations (NNE) to diagnose one cancer by symptoms/signs and subsite. We considered narrow (haemoglobin <11 g/dL men; <10 g/dL women) and broad (<13 g/dL men; <12 g/dL women) anaemia definitions and iron-deficiency anaemia (IDA). RESULTS: One hundred and twenty-seven proximal and 429 distal CRCs were diagnosed. A broad anaemia definition identified 80% of proximal cancers; a narrow definition with IDA identified 39%. In patients with broad definition anaemia and/or abdominal mass, proximal cancer yield and NNE were 4.8% (97/2022) and 21. In patients without broad definition anaemia and/or abdominal mass, with rectal bleeding or increased stool frequency (41% of cohort), proximal cancer yield and NNE were 0.4% (13/3031) and 234. CONCLUSION: Most proximal cancers are accompanied by broad definition anaemia. In patients without broad definition anaemia and/or abdominal mass, with rectal bleeding or increased stool frequency, proximal cancer is rare and FS should suffice.

Adenoma surveillance and colorectal cancer incidence: a retrospective, multicentre, cohort study.

BACKGROUND: Removal of adenomas reduces colorectal cancer incidence and mortality; however, the benefit of surveillance colonoscopy on colorectal cancer risk remains unclear. We examined heterogeneity in colorectal cancer incidence in intermediate-risk patients and the effect of surveillance on colorectal cancer incidence. METHODS: We did this retrospective, multicentre, cohort study using routine lower gastrointestinal endoscopy and pathology data from patients who, after baseline colonoscopy and polypectomy, were diagnosed with intermediate-risk adenomas mostly (>99%) between Jan 1, 1990, and Dec 31, 2010, at 17 hospitals in the UK. These patients are currently offered surveillance colonoscopy at intervals of 3 years. Patients were followed up through to Dec 31, 2014.We assessed the effect of surveillance on colorectal cancer incidence using Cox regression with adjustment for patient, procedural, and polyp characteristics. We defined lower-risk and higher-risk subgroups on the basis of polyp and procedural characteristics identified as colorectal cancer risk factors. We estimated colorectal cancer incidence and standardised incidence ratios (SIRs) using as standard the general population of England in 2007. This trial is registered, number ISRCTN15213649. FINDINGS: 253 798 patients who underwent colonic endoscopy were identified, of whom 11 944 with intermediate-risk adenomas were included in this analysis. After a median follow-up of 7·9 years (IQR 5·6-11·1), 210 colorectal cancers were diagnosed. 5019 (42%) patients did not attend surveillance and 6925 (58%) attended one or more surveillance visits. Compared to no surveillance, one or two surveillance visits were associated with a significant reduction in colorectal cancer incidence rate (adjusted hazard ratio 0·57, 95% CI 0·40-0·80 for one visit; 0·51, 0·31-0·84 for two visits). Without surveillance, colorectal cancer incidence in patients with a suboptimal quality colonoscopy, proximal polyps, or a high-grade or large adenoma (≥20 mm) at baseline (8865 [74%] patients) was significantly higher than in the general population (SIR 1·30, 95% CI 1·06-1·57). By contrast, in patients without these features, colorectal cancer incidence was lower than that of the general population (SIR 0·51, 95% CI 0·29-0·84). INTERPRETATION: Colonoscopy surveillance benefits most patients with intermediate-risk adenomas. However, some patients are already at low risk after baseline colonoscopy and the value of surveillance for them is unclear. FUNDING: National Institute for Health Research Health Technology Assessment, Cancer Research UK.

Accounting for Twins and Other Multiple Births in Perinatal Studies Conducted Using Healthcare Administration Data.

The analysis of perinatal studies is complicated by twins and other multiple births even when they are not the exposure, outcome, or a confounder of interest. Common approaches to handling multiples in studies of infant outcomes include restriction to singletons, counting outcomes at the pregnancy-level (i.e., by counting if at least one twin experienced a binary outcome), or infant-level analysis including all infants and, typically, accounting for clustering of outcomes by using generalised estimating equations or mixed effects models. Several healthcare administration databases only support restriction to singletons or pregnancy-level approaches. For example, in MarketScan insurance claims data, diagnoses in twins are often assigned to a single infant identifier, thereby preventing ascertainment of infant-level outcomes among multiples. Different approaches correspond to different causal questions, produce different estimands, and often rely on different assumptions. We demonstrate the differences that can arise from these different approaches using Monte Carlo simulations, algebraic formulas, and an applied example. Furthermore, we provide guidance on the handling of multiples in perinatal studies when using healthcare administration data.

Systemic Fluoroquinolone Use and Risk of Uveitis or Retinal Detachment.

Importance: Fluoroquinolone use has been associated with increased risk of uveitis and retinal detachment in noninterventional studies, but the findings have been conflicting and causality is unclear. Objective: To estimate the association of systemic fluoroquinolone use with acute uveitis or retinal detachment, using multiple analyses and multiple databases to increase the robustness of results. Design, Setting, and Participants: This cohort study used data from the Clinical Practice Research Datalink Aurum and GOLD UK primary care records databases, which were linked to hospital admissions data. Adults prescribed a fluoroquinolone or a comparator antibiotic, cephalosporin, between April 1997 and December 2019 were included. Adults with uveitis or retinal detachment were analyzed in a separate self-controlled case series. Data analysis was performed from May 2022 to May 2023. Exposures: Systemic fluoroquinolone or comparator antibiotic. Main Outcomes and Measures: The primary outcome was a diagnosis of acute uveitis or retinal detachment. Hazard ratios (HRs) were estimated in the cohort study for the association of fluoroquinolone prescription with either uveitis or retinal detachment, using stabilized inverse probability of treatment weighted Cox regression. Rate ratios (RRs) were estimated in the self-controlled case series, using conditional Poisson regression. Estimates were pooled across databases using fixed-effects meta-analysis. Results: In total, 3 001 256 individuals in Aurum (1 893 561 women [63.1%]; median [IQR] age, 51 [35-68] years) and 434 754 in GOLD (276 259 women [63.5%]; median [IQR] age, 53 [37-70] years) were included in the cohort study. For uveitis, the pooled adjusted HRs (aHRs) for use of fluoroquinolone vs cephalosporin were 0.91 (95% CI, 0.72-1.14) at first treatment episode and 1.07 (95% CI, 0.92-1.25) over all treatment episodes. For retinal detachment, the pooled aHRs were 1.37 (95% CI, 0.80-2.36) at first treatment episode and 1.18 (95% CI, 0.84-1.65) over all treatment episodes. In the self-controlled case series, for uveitis, the pooled adjusted RRs (aRRs) for fluoroquinolone use vs nonuse were 1.13 (95% CI, 0.97-1.31) for 1 to 29 days of exposure, 1.16 (95% CI, 1.00-1.34) for 30 to 59 days, and 0.98 (95% CI, 0.74-1.31) for 60 days for longer. For retinal detachment, pooled aRRs for fluoroquinolone use vs nonuse were 1.15 (95% CI, 0.86-1.54) for 1 to 29 days of exposure, 0.94 (95% CI, 0.69-1.30) for 30 to 59 days, and 1.03 (95% CI, 0.59-1.78) for 60 days or longer. Conclusions and Relevance: These findings do not support an association of systemic fluoroquinolone use with substantively increased risk of uveitis or retinal detachment. Although an association cannot be completely ruled out, these findings indicate that any absolute increase in risk would be small and, hence, of limited clinical importance.

Proton pump inhibitors and myocardial infarction: an application of active comparators in a self-controlled case series.

BACKGROUND: Previous studies investigating potential cardiovascular adverse events of acid-suppressing drugs are susceptible to protopathic bias and confounding. We aimed to investigate the association between short-term risk of myocardial infarction (MI) and proton pump inhibitors (PPIs) using a self-controlled case series (SCCS) with an active comparator. METHODS: We conducted a SCCS using a population-wide database from Hong Kong from 2003-2014. Adult with ≥1 outpatient oral PPI prescription or H2 receptor antagonist (H2RA) and MI during the observation period were included. We used both simple ratio and effect modifier approaches to SCCS with active comparators to obtain comparator adjusted estimates. RESULTS: A total of 2802 and 1889 people with MI who had exposure to PPIs and H2RA were included respectively. We observed a higher risk of MI during days 1-14 following the start of PPI prescription (Incidence rate ratio (IRR): 2.30, 95% confidence interval (CI): 1.76-3.00) versus baseline. Similarly, we observed a higher risk of MI during days 1-14 following the start of H2RA prescription (IRR: 2.46, 95%CI: 1.92-3.16) versus baseline. In the novel SCCS analyses, comparator adjusted estimates were 0.93 (95%CI: 0.57-1.30) and 0.83 (95%CI: 0.58-1.20) during days 1-14 in simple ratio and effect modifier approach, respectively. CONCLUSIONS: We observed no difference in risk of MI associated with PPIs compared with baseline using H2RA as the active comparator. The elevated risk of MI associated with PPIs is likely due to protopathic bias. More studies are required to explore the feasibility of using active comparators in SCCS to address protopathic bias in addition to confounding.

Association Between Fluoroquinolone Use and Hospitalization With Aortic Aneurysm or Aortic Dissection.

Importance: Fluoroquinolone use has been associated with increased hospitalization with aortic aneurysm or dissection in noninterventional studies, but the reason for this observed association is unclear. Objective: To determine the association between fluoroquinolone use and aortic aneurysm or dissection using multiple study designs and multiple databases to increase the robustness of findings. Design, Setting, and Participants: Cohort and case-crossover studies were conducted separately in 2 databases of UK primary care records. Clinical Practice Research Datalink Aurum and GOLD primary care records were linked to hospital admissions data. Adults with a systemic fluoroquinolone or cephalosporin prescription between April 1997 and December 2019 were included in the cohort study. Adults hospitalized with aortic aneurysm or dissection within the eligibility period were included in the case-crossover study. Individuals meeting inclusion criteria in the case-crossover study were matched 1:3 to control individuals on age, sex, index date, and clinical practice to adjust for calendar trends in prescribing. Data were analyzed from January to July 2022. Exposures: Systemic fluoroquinolone or comparator antibiotic. Main Outcomes and Measures: Hazard ratios (HRs) were estimated in the cohort study for the association between prescription of fluoroquinolones and hospitalization with aortic aneurysm or dissection using stabilized inverse probability of treatment-weighted Cox regression. Odds ratios (OR) were estimated in the case-crossover study for the association between systemic fluoroquinolone use and hospitalization with aortic aneurysm or dissection using a conditional logistic regression model. Estimates were pooled across databases using fixed-effects meta-analysis. Results: In the cohort study, we identified 3 134 121 adults in Aurum (mean [SD] age, 52.5 [20.3] years; 1 969 257 [62.8%] female) and 452 086 in GOLD (mean [SD] age, 53.9 [20.2] years; 286 502 [63.4%] female) who were prescribed fluoroquinolones or cephalosporins. In crude analyses, fluoroquinolone relative to cephalosporin use was associated with increased hospitalization with aortic aneurysm or dissection (pooled HR, 1.28; 95% CI, 1.13-1.44; P < .001) but after adjustment for potential confounders, this association disappeared (pooled adjusted HR, 1.03; 95% CI, 0.91-1.17; P = .65). In the case-crossover study, we identified 84 841 individuals hospitalized with aortic aneurysm or dissection in Aurum (mean [SD] age, 75.5 [10.9]; 23 551 [27.8%] female) and 10 357 in GOLD (mean [SD] age, 75.6 [10.5]; 2809 [27.1%] female). Relative to nonuse, fluoroquinolone use was associated with an increase in hospitalization with aortic aneurysm or dissection, but no association was found relative to other antibiotics (vs cephalosporin pooled OR, 1.05; 95% CI, 0.87-1.27; vs trimethoprim, 0.89; 95% CI, 0.75-1.06; vs co-amoxiclav, 0.98; 95% CI, 0.82-1.18). Conclusions and Relevance: The results in this study suggest that estimates of association of fluoroquinolones with aortic aneurysm or dissection may be affected by confounding. When such confounding is accounted for, no association was evident, providing reassurance on the safety of fluoroquinolones with respect to aortic aneurysm or dissection.

A complex interplay between H2A.Z and HP1 isoforms regulates pericentric heterochromatin.

Pericentric heterochromatin (PCH) plays an essential role in the maintenance of genome integrity and alterations in PCH have been linked to cancer and aging. HP1 α, ß, and γ, are hallmarks of constitutive heterochromatin that are thought to promote PCH structure through binding to heterochromatin-specific histone modifications and interaction with a wide range of factors. Among the less understood components of PCH is the histone H2A variant H2A.Z, whose role in the organization and maintenance of PCH is poorly defined. Here we show that there is a complex interplay between H2A.Z and HP1 isoforms in PCH. While the loss of HP1α results in the accumulation of H2A.Z.1 in PCH, which is associated with a significant decrease in its mobile fraction, H2A.Z.1 binds preferentially to HP1ß in these regions. Of note, H2A.Z.1 downregulation results in increased heterochromatinization and instability of PCH, reflected by accumulation of the major epigenetic hallmarks of heterochromatin in these regions and increased frequency of chromosome aberrations related to centromeric/pericentromeric defects. Our studies support a role for H2A.Z in genome stability and unveil a key role of H2A.Z in the regulation of heterochromatin-specific epigenetic modifications through a complex interplay with the HP1 isoforms.

Association between oral anticoagulants and COVID-19-related outcomes: a population-based cohort study.

BACKGROUND: Early evidence has shown that anticoagulant reduces the risk of thrombotic events in those infected with COVID-19. However, evidence of the role of routinely prescribed oral anticoagulants (OACs) in COVID-19 outcomes is limited. AIM: To investigate the association between OACs and COVID-19 outcomes in those with atrial fibrillation and a CHA2DS2-VASc score of 2. DESIGN AND SETTING: On behalf of NHS England, a population-based cohort study was conducted. METHOD: The study used primary care data and pseudonymously-linked SARS-CoV-2 antigen testing data, hospital admissions, and death records from England. Cox regression was used to estimate hazard ratios (HRs) for COVID-19 outcomes comparing people with current OAC use versus non-use, accounting for age, sex, comorbidities, other medications, deprivation, and general practice. RESULTS: Of 71 103 people with atrial fibrillation and a CHA2DS2-VASc score of 2, there were 52 832 current OAC users and 18 271 non-users. No difference in risk of being tested for SARS-CoV-2 was associated with current use (adjusted HR [aHR] 0.99, 95% confidence interval [CI] = 0.95 to 1.04) versus non-use. A lower risk of testing positive for SARS-CoV-2 (aHR 0.77, 95% CI = 0.63 to 0.95) and a marginally lower risk of COVID-19-related death (aHR, 0.74, 95% CI = 0.53 to 1.04) were associated with current use versus non-use. CONCLUSION: Among those at low baseline stroke risk, people receiving OACs had a lower risk of testing positive for SARS-CoV-2 and severe COVID-19 outcomes than non-users; this might be explained by a causal effect of OACs in preventing severe COVID-19 outcomes or unmeasured confounding, including more cautious behaviours leading to reduced infection risk.

Association between living with children and outcomes from covid-19: OpenSAFELY cohort study of 12 million adults in England.

OBJECTIVE: To investigate whether risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and outcomes of coronavirus disease 2019 (covid-19) differed between adults living with and without children during the first two waves of the UK pandemic. DESIGN: Population based cohort study, on behalf of NHS England. SETTING: Primary care data and pseudonymously linked hospital and intensive care admissions and death records from England, during wave 1 (1 February to 31 August 2020) and wave 2 (1 September to 18 December 2020). PARTICIPANTS: Two cohorts of adults (18 years and over) registered at a general practice on 1 February 2020 and 1 September 2020. MAIN OUTCOME MEASURES: Adjusted hazard ratios for SARS-CoV-2 infection, covid-19 related admission to hospital or intensive care, or death from covid-19, by presence of children in the household. RESULTS: Among 9 334 392adults aged 65 years and under, during wave 1, living with children was not associated with materially increased risks of recorded SARS-CoV-2 infection, covid-19 related hospital or intensive care admission, or death from covid-19. In wave 2, among adults aged 65 years and under, living with children of any age was associated with an increased risk of recorded SARS-CoV-2 infection (hazard ratio 1.06 (95% confidence interval 1.05 to 1.08) for living with children aged 0-11 years; 1.22 (1.20 to 1.24) for living with children aged 12-18 years) and covid-19 related hospital admission (1.18 (1.06 to 1.31) for living with children aged 0-11; 1.26 (1.12 to 1.40) for living with children aged 12-18). Living with children aged 0-11 was associated with reduced risk of death from both covid-19 and non-covid-19 causes in both waves; living with children of any age was also associated with lower risk of dying from non-covid-19 causes. For adults 65 years and under during wave 2, living with children aged 0-11 years was associated with an increased absolute risk of having SARS-CoV-2 infection recorded of 40-60 per 10 000 people, from 810 to between 850 and 870, and an increase in the number of hospital admissions of 1-5 per 10 000 people, from 160 to between 161 and 165. Living with children aged 12-18 years was associated with an increase of 160-190 per 10 000 in the number of SARS-CoV-2 infections and an increase of 2-6 per 10 000 in the number of hospital admissions. CONCLUSIONS: In contrast to wave 1, evidence existed of increased risk of reported SARS-CoV-2 infection and covid-19 outcomes among adults living with children during wave 2. However, this did not translate into a materially increased risk of covid-19 mortality, and absolute increases in risk were small.

Association between warfarin and COVID-19-related outcomes compared with direct oral anticoagulants: population-based cohort study.

BACKGROUND: Thromboembolism has been reported as a consequence of severe COVID-19. Although warfarin is a commonly used anticoagulant, it acts by antagonising vitamin K, which is low in patients with severe COVID-19. To date, the clinical evidence on the impact of regular use of warfarin on COVID-19-related thromboembolism is lacking. METHODS: On behalf of NHS England, we conducted a population-based cohort study investigating the association between warfarin and COVID-19 outcomes compared with direct oral anticoagulants (DOACs). We used the OpenSAFELY platform to analyse primary care data and pseudonymously linked SARS-CoV-2 antigen testing data, hospital admissions and death records from England. We used Cox regression to estimate hazard ratios (HRs) for COVID-19-related outcomes comparing warfarin with DOACs in people with non-valvular atrial fibrillation. We also conducted negative control outcome analyses (being tested for SARS-CoV-2 and non-COVID-19 death) to assess the potential impact of confounding. RESULTS: A total of 92,339 warfarin users and 280,407 DOAC users were included. We observed a lower risk of all outcomes associated with warfarin versus DOACs [testing positive for SARS-CoV-2, HR 0.73 (95% CI 0.68-0.79); COVID-19-related hospital admission, HR 0.75 (95% CI 0.68-0.83); COVID-19-related deaths, HR 0.74 (95% CI 0.66-0.83)]. A lower risk of negative control outcomes associated with warfarin versus DOACs was also observed [being tested for SARS-CoV-2, HR 0.80 (95% CI 0.79-0.81); non-COVID-19 deaths, HR 0.79 (95% CI 0.76-0.83)]. CONCLUSIONS: Overall, this study shows no evidence of harmful effects of warfarin on severe COVID-19 disease.

Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform.

BACKGROUND: Hydroxychloroquine has been shown to inhibit entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into epithelial cells in vitro, but clinical studies found no evidence of reduced mortality when treating patients with COVID-19. We aimed to evaluate the effectiveness of hydroxychloroquine for prevention of COVID-19 mortality, as opposed to treatment for the disease. METHODS: We did a prespecified observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, which covers approximately 40% of the general population in England, UK. We included all adults aged 18 years and older registered with a general practice for 1 year or more on March 1, 2020. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use before the COVID-19 outbreak in England (considered as March 1, 2020) compared with non-users of hydroxychloroquine and risk of COVID-19 mortality among people with rheumatoid arthritis or systemic lupus erythematosus. Model adjustment was informed by a directed acyclic graph. FINDINGS: Between Sept 1, 2019, and March 1, 2020, of 194 637 people with rheumatoid arthritis or systemic lupus erythematosus, 30 569 (15·7%) received two or more prescriptions of hydroxychloroquine. Between March 1 and July 13, 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0·23% (95% CI 0·18 to 0·29) among users and 0·22% (0·20 to 0·25) among non-users; an absolute difference of 0·008% (-0·051 to 0·066). After accounting for age, sex, ethnicity, use of other immunosuppressive drugs, and geographical region, no association with COVID-19 mortality was observed (HR 1·03, 95% CI 0·80 to 1·33). We found no evidence of interactions with age or other immunosuppressive drugs. Quantitative bias analyses indicated that our observed associations were robust to missing information for additional biologic treatments for rheumatological disease. We observed similar associations with the negative control outcome of non-COVID-19 mortality. INTERPRETATION: We found no evidence of a difference in COVID-19 mortality among people who received hydroxychloroquine for treatment of rheumatological disease before the COVID-19 outbreak in England. Therefore, completion of randomised trials investigating pre-exposure prophylactic use of hydroxychloroquine for prevention of severe outcomes from COVID-19 are warranted. FUNDING: Medical Research Council.

Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform.

BACKGROUND: Early descriptions of patients admitted to hospital during the COVID-19 pandemic showed a lower prevalence of asthma and chronic obstructive pulmonary disease (COPD) than would be expected for an acute respiratory disease like COVID-19, leading to speculation that inhaled corticosteroids (ICSs) might protect against infection with severe acute respiratory syndrome coronavirus 2 or the development of serious sequelae. We assessed the association between ICS and COVID-19-related death among people with COPD or asthma using linked electronic health records (EHRs) in England, UK. METHODS: In this observational study, we analysed patient-level data for people with COPD or asthma from primary care EHRs linked with death data from the Office of National Statistics using the OpenSAFELY platform. The index date (start of follow-up) for both cohorts was March 1, 2020; follow-up lasted until May 6, 2020. For the COPD cohort, individuals were eligible if they were aged 35 years or older, had COPD, were a current or former smoker, and were prescribed an ICS or long-acting ß agonist plus long-acting muscarinic antagonist (LABA-LAMA) as combination therapy within the 4 months before the index date. For the asthma cohort, individuals were eligible if they were aged 18 years or older, had been diagnosed with asthma within 3 years of the index date, and were prescribed an ICS or short-acting ß agonist (SABA) only within the 4 months before the index date. We compared the outcome of COVID-19-related death between people prescribed an ICS and those prescribed alternative respiratory medications: ICSs versus LABA-LAMA for the COPD cohort, and low-dose or medium-dose and high-dose ICSs versus SABAs only in the asthma cohort. We used Cox regression models to estimate hazard ratios (HRs) and 95% CIs for the association between exposure categories and the outcome in each population, adjusted for age, sex, and all other prespecified covariates. We calculated e-values to quantify the effect of unmeasured confounding on our results. FINDINGS: We identified 148 557 people with COPD and 818 490 people with asthma who were given relevant respiratory medications in the 4 months before the index date. People with COPD who were prescribed ICSs were at increased risk of COVID-19-related death compared with those prescribed LABA-LAMA combinations (adjusted HR 1·39 [95% CI 1·10-1·76]). Compared with those prescribed SABAs only, people with asthma who were prescribed high-dose ICS were at an increased risk of death (1·55 [1·10-2·18]), whereas those given a low or medium dose were not (1·14 [0·85-1·54]). Sensitivity analyses showed that the apparent harmful association we observed could be explained by relatively small health differences between people prescribed ICS and those not prescribed ICS that were not recorded in the database (e value lower 95% CI 1·43). INTERPRETATION: Our results do not support a major role for regular ICS use in protecting against COVID-19-related death among people with asthma or COPD. Observed increased risks of COVID-19-related death can be plausibly explained by unmeasured confounding due to disease severity. FUNDING: UK Medical Research Council.

Effect of once-only flexible sigmoidoscopy screening on the outcomes of subsequent faecal occult blood test screening.

OBJECTIVE: To investigate the outcomes of biennial guaiac faecal occult blood test (gFOBT) screening after once-only flexible sigmoidoscopy (FS) screening. METHODS: Between 1994 and 1999, as part of the UK FS Screening Trial (UKFSST), adults aged 55-64 were randomly allocated to an intervention group (offered FS screening) or a control group (not contacted). From 2006, a subset of UKFSST participants (20,895/44,041 intervention group; 41,497/87,149 control group) were invited to biennial gFOBT screening by the English Bowel Cancer Screening Programme. We analysed gFOBT uptake, test positivity, yield of colorectal cancer (CRC), and positive predictive value (PPV) for CRC, advanced adenomas (AAs), and advanced colorectal neoplasia (ACN: AA/CRC). RESULTS: Uptake of gFOBT at first invitation was 1.9% lower (65.7% vs. 67.6%, p < 0.01) among intervention versus control group participants. Positivity was 0.4% lower (2.0% vs. 2.4%, p < 0.01) and CRC yield was 0.08% lower (0.19% vs. 0.27%, p = 0.14). PPVs were also lower in the intervention versus control group, at 10.3% vs. 12.3% ( p = 0.44) for CRC, 22.7% vs. 31.4% ( p < 0.01) for AA, and 33.0% vs. 43.7% ( p < 0.01) for ACN. Among those who refused FS ( n = 5532), gFOBT uptake at first invitation was 47.7%, CRC yield was 0.25%, and PPV for ACN was 46.2%. Among FS attenders ( n = 15,363), uptake was 72.2%, CRC yield was 0.18%, and PPV for ACN was 27.9%. CONCLUSIONS: Uptake, positivity and PPV of gFOBT screening were reduced following prior offer of FS screening. However, a quarter of FS screened participants receiving a diagnostic examination after positive gFOBT were diagnosed with ACN.

Association of Relative Age in the School Year With Diagnosis of Intellectual Disability, Attention-Deficit/Hyperactivity Disorder, and Depression.

IMPORTANCE: Young relative age within the school year has previously been associated with attention-deficit/hyperactivity disorder (ADHD) diagnosis and, based on limited evidence, diagnosis of intellectual disability. No study to date has examined the association between relative age and diagnosis of depression. OBJECTIVES: To estimate the associations with intellectual disability and ADHD and investigate a potential novel association between relative age and childhood depression. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study of 1 042 106 children aged 4 to 15 years used electronic record data collected before January 3, 2017, from more than 700 general practices contributing to the UK Clinical Practice Research Datalink. Multivariable Cox proportional hazards regression modeling was used to explore the association between relative age and the incidence of intellectual disability, ADHD, and depression before age 16 years. Data were analyzed between July 2017 and January 2019. EXPOSURES: Relative age within school year determined by month of birth and categorized into four 3-month groups. MAIN OUTCOMES AND MEASURES: Intellectual disability, ADHD, and depression. RESULTS: In the total cohort of 1 042 106 children, 532 876 were male (51.1%) and the median age at study entry was 4.0 years (interquartile range, 4.0-5.0). There was evidence that being born in the last quarter of the school year (ie, being the youngest group in a school year) was associated with diagnosis of intellectual disability (adjusted hazard ratio [aHR], 1.30; 95% CI, 1.18-1.42), ADHD (aHR, 1.36; 95% CI, 1.28-1.45), and depression (aHR, 1.31; 95% CI, 1.08-1.59) compared with being born in the first quarter. A graded association was seen with intermediate age groups at a smaller increased risk of each diagnosis compared with the oldest group, with aHRs for intellectual disability for those born in the second quarter of 1.06 (95% CI, 0.96-1.17) and for those born in the third quarter of 1.20 (95% CI, 1.09-1.32); aHRs for ADHD for those born in the second quarter of 1.15 (95% CI, 1.08-1.23) and for those born in the third quarter of 1.31 (95% CI, 1.23-1.40); and aHRs for depression for those born in the second quarter of 1.05 (95% CI, 0.85-1.29) and for those born in the third quarter of 1.13 (95% CI, 0.92-1.38). CONCLUSIONS AND RELEVANCE: In this study, relative youth status in the school year is associated with an increased risk of diagnosis of ADHD, intellectual disability, and depression in childhood. Further research into clinical and policy interventions to minimize these associations appears to be needed.

Deletion of HP1γ in cardiac myocytes affects H4K20me3 levels but does not impact cardiac growth.

BACKGROUND: Heterochromatin, which is formed when tri-methyl lysine 9 of histone H3 (H3K9me3) is bound by heterochromatin 1 proteins (HP1s), plays an important role in differentiation and senescence by silencing cell cycle genes. Cardiac myocytes (CMs) accumulate heterochromatin during differentiation and demethylation of H3K9me3 inhibits cell cycle gene silencing and cell cycle exit in CMs; however, it is unclear if this process is mediated by HP1s. In this study, we created a conditional CM-specific HP1 gamma (HP1γ) knockout (KO) mouse model and tested whether HP1γ is required for cell cycle gene silencing and cardiac growth. RESULTS: HP1γ KO mice were generated by crossing HP1γ floxed mice (fl) with mice expressing Cre recombinase driven by the Nkx2.5 (cardiac progenitor gene) promoter (Cre). We confirmed that deletion of critical exons of HP1γ led to undetectable levels of HP1γ protein in HP1γ KO (Cre;fl/fl) CMs. Analysis of cardiac size and function by echo revealed no significant differences between HP1γ KO and control (WT, Cre, fl/fl) mice. No significant difference in expression of cell cycle genes or cardiac-specific genes was observed. Global transcriptome analysis demonstrated a very moderate effect of HP1γ deletion on global gene expression, with only 51 genes differentially expressed in HP1γ KO CMs. We found that HP1ß protein, but not HP1α, was significantly upregulated and that subnuclear localization of HP1ß to perinuclear heterochromatin was increased in HP1γ KO CMs. Although HP1γ KO had no effect on H3K9me3 levels, we found a significant reduction in another major heterochromatin mark, tri-methylated lysine 20 of histone H4 (H4K20me3). CONCLUSIONS: These data indicate that HP1γ is dispensable for cell cycle exit and normal cardiac growth but has a significant role in maintaining H4K20me3 and regulating a limited number of genes in CMs.