Correction: Migraine and risk of premature myocardial infarction and stroke among men and women: A Danish population-based cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1004238.].

Excess Mortality Calculations to Assess the Impact of the COVID-19 Pandemic: Concepts and Methodological Issues.

We discuss some intriguing methodological aspects of excess mortality analyses, which have been widely used to describe the impact of the COVID-19 pandemic. We describe the main ways of presenting excess mortality: as a mortality rate (incidence rate) or as a percentage increase (relative risk or rate ratio). We discuss what should be regarded as the null value of excess mortality (i.e., when countries or regions can be judged as having fared equally well) and when age and sex standardization, adjustment for other determinants of the spread of a pandemic, or both is necessary. We discuss the level of detail by time and place and person that may be necessary. We note that an excess mortality comparison is essentially a difference-in-differences analysis. We conclude that, although one cannot rule out using excess mortality analyses for causal effect estimates, such analyses will remain most fruitful for generating hypotheses about both the efficiency of measures to curtail the pandemic and factors that cannot be influenced. Nevertheless, a judicious use of arguments and counterarguments can then lead to identifying best practices for various situations. (Am J Public Health. 2024;114(6):593-598. https://doi.org/10.2105/AJPH.2024.307572).

Migraine and risk of premature myocardial infarction and stroke among men and women: A Danish population-based cohort study.

BACKGROUND: Migraine carries risk of myocardial infarction (MI) and stroke. The risk of premature MI (i.e., among young adults) and stroke differs between men and women; previous studies indicate that migraine is mainly associated with an increased risk of stroke among young women. The aim of this study was to examine impact of migraine on the risk of premature (age ≤60 years) MI and ischemic/hemorrhagic stroke among men and women. METHODS AND FINDINGS: Using Danish medical registries, we conducted a nationwide population-based cohort study (1996 to 2018). Redeemed prescriptions for migraine-specific medication were used to identify women with migraine (n = 179,680) and men with migraine (n = 40,757). These individuals were matched on sex, index year, and birth year 1:5 with a random sample of the general population who did not use migraine-specific medication. All individuals were required to be between 18 and 60 years old. Median age was 41.5 years for women and 40.3 years for men. The main outcome measures to assess impact of migraine were absolute risk differences (RDs) and hazard ratios (HRs) with 95% confidence intervals (CIs) of premature MI, ischemic, and hemorrhagic stroke, comparing individuals with migraine to migraine-free individuals of the same sex. HRs were adjusted for age, index year, and comorbidities. The RD of premature MI for those with migraine versus no migraine was 0.3% (95% CI [0.2%, 0.4%]; p < 0.001) for women and 0.3% (95% CI [-0.1%, 0.6%]; p = 0.061) for men. The adjusted HR was 1.22 (95% CI [1.14, 1.31]; p < 0.001) for women and 1.07 (95% CI [0.97, 1.17]; p = 0.164) for men. The RD of premature ischemic stroke for migraine versus no migraine was 0.3% (95% CI [0.2%, 0.4%]; p < 0.001) for women and 0.5% (95% CI [0.1%, 0.8%]; p < 0.001) for men. The adjusted HR was 1.21 (95% CI [1.13, 1.30]; p < 0.001) for women and 1.23 (95% CI [1.10, 1.38]; p < 0.001) for men. The RD of premature hemorrhagic stroke for migraine versus no migraine was 0.1% (95% CI [0.0%, 0.2%]; p = 0.011) for women and -0.1% (95% CI [-0.3%, 0.0%]; p = 0.176) for men. The adjusted HR was 1.13 (95% CI [1.02, 1.24]; p = 0.014) for women and 0.85 (95% CI [0.69, 1.05]; p = 0.131) for men. The main limitation of this study was the risk of misclassification of migraine, which could lead to underestimation of the impact of migraine on each outcome. CONCLUSIONS: In this study, we observed that migraine was associated with similarly increased risk of premature ischemic stroke among men and women. For premature MI and hemorrhagic stroke, there may be an increased risk associated with migraine only among women.

A Test-Negative Design with Additional Population Controls Can Be Used to Rapidly Study Causes of the SARS-CoV-2 Epidemic.

Testing of symptomatic persons for infection with severe acute respiratory syndrome coronavirus-2 is occurring worldwide. We propose two types of case-control studies that can be carried out jointly in test settings for symptomatic persons. The first, the test-negative case-control design (TND) is the easiest to implement; it only requires collecting information about potential risk factors for Coronavirus Disease 2019 (COVID-19) from the tested symptomatic persons. The second, standard case-control studies with population controls, requires the collection of data on one or more population controls for each person who is tested in the test facilities, so that test-positives and test-negatives can each be compared with population controls. The TND will detect differences in risk factors between symptomatic persons who have COVID-19 (test-positives) and those who have other respiratory infections (test-negatives). However, risk factors with effect sizes of equal magnitude for both COVID-19 and other respiratory infections will not be identified by the TND. Therefore, we discuss how to add population controls to compare with the test-positives and the test-negatives, yielding two additional case-control studies. We describe two options for population control groups: one composed of accompanying persons to the test facilities, the other drawn from existing country-wide healthcare databases. We also describe other possibilities for population controls. Combining the TND with population controls yields a triangulation approach that distinguishes between exposures that are risk factors for both COVID-19 and other respiratory infections, and exposures that are risk factors for just COVID-19. This combined design can be applied to future epidemics, but also to study causes of nonepidemic disease.

COSMOS-E: Guidance on conducting systematic reviews and meta-analyses of observational studies of etiology.

BACKGROUND: To our knowledge, no publication providing overarching guidance on the conduct of systematic reviews of observational studies of etiology exists. METHODS AND FINDINGS: Conducting Systematic Reviews and Meta-Analyses of Observational Studies of Etiology (COSMOS-E) provides guidance on all steps in systematic reviews of observational studies of etiology, from shaping the research question, defining exposure and outcomes, to assessing the risk of bias and statistical analysis. The writing group included researchers experienced in meta-analyses and observational studies of etiology. Standard peer-review was performed. While the structure of systematic reviews of observational studies on etiology may be similar to that for systematic reviews of randomised controlled trials, there are specific tasks within each component that differ. Examples include assessment for confounding, selection bias, and information bias. In systematic reviews of observational studies of etiology, combining studies in meta-analysis may lead to more precise estimates, but such greater precision does not automatically remedy potential bias. Thorough exploration of sources of heterogeneity is key when assessing the validity of estimates and causality. CONCLUSION: As many reviews of observational studies on etiology are being performed, this document may provide researchers with guidance on how to conduct and analyse such reviews.

Test-Negative Designs: Differences and Commonalities with Other Case-Control Studies with "Other Patient" Controls.

Test-negative studies recruit cases who attend a healthcare facility and test positive for a particular disease; controls are patients undergoing the same tests for the same reasons at the same healthcare facility and who test negative. The design is often used for vaccine efficacy studies, but not exclusively, and has been posited as a separate type of study design, different from case-control studies because the controls are not sampled from a wider source population. However, the design is a special case of a broader class of case-control designs that identify cases and sample "other patient" controls from the same healthcare facilities. Therefore, we consider that new insights into the test-negative design can be obtained by viewing them as case-control studies with "other patient" controls; in this context, we explore differences and commonalities, to better define the advantages and disadvantages of the test-negative design in various circumstances. The design has the advantage of similar participation rates, information quality and completeness, referral/catchment areas, initial presentation, diagnostic suspicion tendencies, and preferences by doctors. Under certain assumptions, valid population odds ratios can be estimated with the test-negative design, just as with case-control studies with "other patient" controls. Interestingly, directed acyclic graphs (DAGs) are not completely helpful in explaining why the design works. The use of test-negative designs may not completely resolve all potential biases, but they are a valid study design option, and will in some circumstances lead to less bias, as well as often the most practical one.

Exposure Opportunity: The Advantages of Including Men in Analyses of Female-Related Risk Factors.

Intuitively, researchers do not include subjects who do not have the opportunity to be exposed, such as men in studies on oral contraceptives (OCs). We aimed to explore in which situations it is nevertheless beneficial to do so. We considered the effect of including men in case-control analyses of 8 different hypothetical data sets on the effect of OC use and venous thrombosis. In all scenarios, OC use was the exposure of interest, sex the factor that determined exposure opportunity, and air travel another risk factor. In some of these scenarios, sex and air travel were included as confounders or effect modifiers. Logistic regression was used to estimate odds ratios. Standard errors of the estimated log odds ratios, including and excluding men, were compared. We also studied the effect of including men using data from 1999-2004 from a case-control study on risk factors for venous thrombosis, conducted in the Netherlands. In all hypothetical examples, and in the real-data study, addition of men to the analysis yielded the same odds ratios when correctly adjusting for confounding. Moreover, use of additional subjects often led to more precise estimates. We suggest that subjects who do not have the opportunity to be exposed should not routinely be excluded from epidemiologic studies.

Risk of venous and arterial thrombotic events in patients diagnosed with superficial vein thrombosis: a nationwide cohort study.

Recently, it has become apparent that superficial vein thrombosis (SVT) can have serious complications. However, the magnitude of the risk of subsequent deep venous and arterial thrombotic events remains unknown. We examined this in a nationwide population-based setting during a period when SVT was not treated routinely with anticoagulants. The Danish National Registry of Patients, covering all Danish hospitals, was used to identify 10 973 patients with a first-time diagnosis of SVT between 1980 and 2012. A comparison cohort of 515 067 subjects, matched by age, gender, and calendar year, was selected from the general Danish population. Outcomes were venous thromboembolism, acute myocardial infarction, ischemic stroke, and death. During median follow-up of 7 years, the incidence rate of venous thromboembolism was 18.0/1000 person-years (95% confidence interval [CI], 17.2-18.9). The highest risk occurred in the first 3 months (3.4%; 95% CI, 3.0-3.7). Compared with the general population, the hazard ratio was 71.4 (95% CI, 60.2-84.7) in this period, steadily decreasing to 5.1 (95% CI 4.6-5.5), 5 years after the SVT. The hazard ratios for acute myocardial infarction, stroke, and death were 1.2 (95% CI, 1.1-1.3), 1.3 (95% CI, 1.2-1.4), and 1.3 (95% CI, 1.2-1.3), respectively, with the highest risk also shortly after SVT. These data indicate the prognostic importance of SVT and may form the basis for clinical decision-making regarding anticoagulation.

Instrumental variable analysis as a complementary analysis in studies of adverse effects: venous thromboembolism and second-generation versus third-generation oral contraceptives.

PURPOSE: A potentially useful role for instrumental variable (IV) analysis may be as a complementary analysis to assess the presence of confounding when studying adverse drug effects. There has been discussion on whether the observed increased risk of venous thromboembolism (VTE) for third-generation oral contraceptives versus second-generation oral contraceptives could be (partially) attributed to confounding. We investigated how prescribing preference IV estimates compare with conventional estimates. METHODS: Women in the Clinical Practice Research Database who started a second-generation or third-generation oral contraceptive from 1989 to 2013 were included. Ordinary least squares and two-stage least squares regression were used to estimate risk differences in VTE. Cox regression and IV for Cox proportional hazards regression were used to calculate hazard ratios (HR). The instrument used was the proportion of prescriptions for third-generation oral contraceptives by the general practitioner in the year preceding the current prescription. RESULTS: All analyses pointed in the direction of an increased VTE risk for third-generation oral contraceptives. The adjusted HR from the conventional Cox regression was 1.62 (95% confidence interval 1.16-2.27) and the fully adjusted HR from the IV Cox regression was 3.45 (95% confidence interval; 0.97-11.7), showing a larger risk and wider confidence intervals in the IV analysis. CONCLUSIONS: The similarity in direction of results from the IV analyses and conventional analyses suggests that major confounding is unlikely. IV analysis can be a useful complementary analysis to assess the presence of confounding in studies of adverse drug effects in very large databases.

Physician's preference-based instrumental variable analysis: is it valid and useful in a moderate-sized study?

BACKGROUND: Instrumental variable methods can potentially circumvent the unmeasured confounding inherent in observational data analyses. METHODS: We investigated the validity and usefulness of physician's preference instrumental variable analysis in the setting of a moderate-sized clinical study. Using routine care data from 476 elective cardiac surgery patients, we assessed the effect of preoperative corticosteroids on mechanical ventilation time and duration of intensive care and hospital stay, occurrence of infections, atrial fibrillation, heart failure, and delirium. RESULTS: Although results of the physician's preference-based instrumental variable analysis corresponded in direction to results of a recent large randomized trial of the same therapy, the instrumental variable estimates showed much larger effects with very wide confidence intervals. CONCLUSION: The lesser statistical precision limits the usefulness of instrumental variable analysis in a study that might be of sufficient size for conventional analyses, even if a strong and plausible instrument is available.

Combined Impact of Migraine and Pregnancy-Induced Hypertension on Long-term Risk of Premature Myocardial Infarction and Stroke.

BACKGROUND AND OBJECTIVES: Migraine and pregnancy-induced hypertension (PIH) are known to increase cardiovascular risk on their own. However, evidence is limited on the combined impact of migraine and PIH on risk of cardiovascular disease. The aim of this study was to examine the combined impact of migraine and PIH on risk of premature (age 60 years and younger) major adverse cardiovascular and cerebrovascular events (MACCE), a composite end point consisting of myocardial infarction, stroke, or death due to one of these diseases. METHODS: We conducted a population-based cohort study in Denmark (1996-2018) among women who had delivered at least one child. This population was stratified into 4 cohorts: women with neither migraine nor PIH, women with migraine, women with PIH, and women with both migraine and PIH. As a measure of absolute risk, we computed the 20-year cumulative incidence of premature MACCE, treating death by other causes than myocardial infarction and stroke as a competing risk. We used Cox regression to compute 20-year adjusted hazard ratios (HRs) of premature MACCE. Women with neither migraine nor PIH served as the comparison cohort. RESULTS: The 20-year absolute risk of premature MACCE was 1.3% (95% CI 1.2%; 1.3%) for women without migraine and without PIH (n = 1,288,541), 2.2% (95% CI 2.0%; 2.4%) for women with migraine (n = 54,827), 2.8% (95% CI 2.6%; 3.1%) for women with PIH (n = 49,008), and 3.1% (95% CI 2.1%; 4.4%) for women with both migraine and PIH (n = 3,140). The adjusted HR of premature MACCE was 1.66 (95% confidence interval [CI] 1.50-1.84) for women with migraine, 2.76 (95% CI 2.52-3.03) for women with PIH, and 2.41 (95% CI 1.61-3.61) for women with both migraine and PIH. DISCUSSION: Migraine and PIH separately increased the risk of premature MACCE. The risk of premature MACCE among women who had both migraine and PIH was similar to that among women with PIH only.

Report on the Joint Workshop on the Relations between Health Inequalities, Ageing and Multimorbidity, Iceland, May 3-4, 2023.

This paper is a summary of key presentations from a workshop in Iceland on May 3-4, 2023 arranged by Aarhus University and with participation of the below-mentioned scientists. Below you will find the key messages from the presentations made by: Professor Jan Vandenbroucke, Department of Clinical Epidemiology, Aarhus University, Emeritus Professor, Leiden University; Honorary Professor, London School of Hygiene & Tropical Medicine, UKProfessor, Chair Henrik Toft Sørensen, Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, DenmarkProfessor David H. Rehkopf, Director, the Stanford Center for Population Health Sciences, Stanford University, CA., USProfessor Jaimie Gradus, Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, USProfessor Johan Mackenbach, Emeritus Professor, Department of Public Health, Erasmus University Rotterdam, HollandProfessor, Chair M Maria Glymour, Department of Epidemiology, Boston University School of Public Health, Boston University, Boston, Massachusetts, USProfessor, Dean Sandro Galea, School of Public Health, Boston University, Boston, Massachusetts, USProfessor Victor W. Henderson, Departments of Epidemiology & Population Health and of Neurology & Neurological Sciences, Stanford University, Stanford, CA, US; Department of Clinical Epidemiology, Aarhus University, Aarhus, DK.

Re-using Mini-Sentinel data following rapid assessments of potential safety signals via modular analytic programs.

The U.S. Food and Drug Administration (FDA)'s Mini-Sentinel pilot has created a distributed data system with over 125 million lives and nearly 350 million person-years of observation time. The pilot allows the FDA to use modular analytic programs to assess suspected safety signals quickly. The FDA convened a committee to assess the implications of such rapid assessments on subsequent analyses of the same product-outcome pair using the same data. The committee offers several non-binding recommendations based on the strength of the knowledge of the suspected association before running the analysis: signal generation (an analysis with no prior), signal refinement (an analysis with a weak or moderate prior), and signal evaluation (an analysis with a strong prior). The committee believes that modular programs (MPs) are most useful for signal refinement. If MPs are used for analyses with no or weak/moderate priors, the committee members generally agree that the data may be re-used if certain conditions are met. When there is a strong prior, the committee recommends that a protocol-based assessment be used; Mini-Sentinel data may be analyzed by MPs and re-used only under very uncommon circumstances. The committee agrees that any subsequent assessment of the same product-outcome pair that follows an MP analysis should not be interpreted as independent confirmation of the association, such as would be established via replication of the same product-outcome association in two different populations. Instead, the follow-up assessment should be interpreted as an analysis that has reduced insofar as possible systematic errors that may have been present or residual in the original MP analysis. The committee also discussed how this general framework may apply to two completed rapid assessments of dabigatran and bleeding risk and of olmesartan and celiac disease risk.

Distinguishing case series from cohort studies.

Case series are a commonly reported study design, but the label "case series" is used inconsistently and sometimes incorrectly. Mislabeling impairs the appropriate indexing and sorting of evidence. This article tries to clarify the concept of case series and proposes a way to distinguish them from cohort studies. In a cohort study, patients are sampled on the basis of exposure and are followed over time, and the occurrence of outcomes is assessed. A cohort study may include a comparison group, although this is not a necessary feature. A case series may be a study that samples patients with both a specific outcome and a specific exposure, or one that samples patients with a specific outcome and includes patients regardless of whether they have specific exposures. Whereas a cohort study, in principle, enables the calculation of an absolute risk or a rate for the outcome, such a calculation is not possible in a case series.

Thromboembolic events, bleeding, and mortality in patients with cerebral venous thrombosis: a nationwide cohort study.

Cerebral venous thrombosis (CVT) predominantly affects young to middle-aged women. Scarce data exist regarding the long-term prognosis. We examined the clinical course of patients with CVT overall and according to their age and sex. Using Danish registries, we identified all patients with a first-time primary inpatient diagnosis of CVT from 1996-2018 (N = 653; median age, 41 years; 67% women) and individuals from the general population matched for age, sex, and calendar year (N = 65 300). Patients with CVT were at an increased risk of venous thromboembolism (VTE) at other sites, ischemic stroke, major bleeding, and mortality. For both sexes, the increased risks of VTE at other sites were most prominent among younger patients (18-54 years), whereas the increased risks of ischemic stroke, major bleeding, and mortality were most prominent among older patients (≥55 years). Among young women, the 10-year risks of VTE at other sites for patients with CVT compared with members of the matched cohort were 2.2% vs 0.4% (risk difference, 1.8%; 95% confidence interval [CI], 0.0-3.6). Among older women, compared with members of the matched cohort, the 10-year risks were 12.8% vs 3.1% (risk difference, 9.7%; 95% CI, 1.6-17.9) for ischemic stroke, 11.1% vs 4.6% (risk difference, 6.5%; 95% CI, -1.0 to 14.1) for major bleeding, and 43.1% vs 26.7% (risk difference, 16.4%; 95% CI, 3.7-29.1) for all-cause mortality. The risk of myocardial infarction was not elevated. Clinicians should be aware of the importance of age and sex heterogeneity in the prognosis of CVT.