A time-varying shared frailty model with application to infectious diseases

We propose a new parametric time-varying shared frailty model to represent changes over time in population heterogeneity, for use with bivariate current status data. The model uses a power transformation of a time-invariant frailty U, and is particularly convenient when U is a member of the generalized gamma family. This model avoids some shortcomings of a previously suggested time-varying frailty model, notably time-dependent support. We describe some key properties of the model, including its relative frailty variance function in different settings and how the model can be fitted to data. We describe several applications to shared frailty modeling of bivariate current status data on infectious diseases, in which the frailty represents age-dependent heterogeneity in contact rates or susceptibility to infection

Self-controlled case series with multiple event types

Self-controlled case series methods for events that may be classified as one of several types are described. When the event is non-recurrent, the different types correspond to competing risks. It is shown that, under circumstances that are likely to arise in practical applications, the SCCS multi-type likelihood reduces to the product of the type-specific likelihoods. For recurrent events, this applies whether or not the marginal type-specific counts are dependent. As for the standard SCCS method, a rare disease assumption is required for non-recurrent events. Several forms of this assumption are investigated by simulation. The methods are applied to data on MMR vaccine and convulsions (febrile and non-febrile), and to data on thiazolidinediones and fractures (at different sites)

The methodology of self-controlled case series studies

The self-controlled case series method is increasingly being used in pharmacoepidemiology, particularly in vaccine safety studies. This method is typically used to evaluate the association between a transient exposure and an acute event, using only cases. We present both parametric and semiparametric models using a motivating example on MMR vaccine and bleeding disorders. We briefly describe approaches for interferent events and a sequential version of the method for prospective surveillance of drug safety. The efficiency of the self-controlled case series method is compared to the that of cohort and case control studies. Some further extensions, to long or indefinite exposures and to bivariate counts, are described

Risk of myocardial infarction and stroke after acute infection or vaccination.

BACKGROUND: There is evidence that chronic inflammation may promote atherosclerotic disease. We tested the hypothesis that acute infection and vaccination increase the short-term risk of vascular events. METHODS: We undertook within-person comparisons, using the case-series method, to study the risks of myocardial infarction and stroke after common vaccinations and naturally occurring infections. The study was based on the United Kingdom General Practice Research Database, which contains computerized medical records of more than 5 million patients. RESULTS: A total of 20,486 persons with a first myocardial infarction and 19,063 persons with a first stroke who received influenza vaccine were included in the analysis. There was no increase in the risk of myocardial infarction or stroke in the period after influenza, tetanus, or pneumococcal vaccination. However, the risks of both events were substantially higher after a diagnosis of systemic respiratory tract infection and were highest during the first three days (incidence ratio for myocardial infarction, 4.95; 95 percent confidence interval, 4.43 to 5.53; incidence ratio for stroke, 3.19; 95 percent confidence interval, 2.81 to 3.62). The risks then gradually fell during the following weeks. The risks were raised significantly but to a lesser degree after a diagnosis of urinary tract infection. The findings for recurrent myocardial infarctions and stroke were similar to those for first events. CONCLUSIONS: Our findings provide support for the concept that acute infections are associated with a transient increase in the risk of vascular events. By contrast, influenza, tetanus, and pneumococcal vaccinations do not produce a detectable increase in the risk of vascular events

Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19 : nationwide self-controlled cases series and matched cohort study

Y OBJECTIVE To quantify the risk of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19. DESIGN Self-controlled case series and matched cohort study. SETTING National registries in Sweden. PARTICIPANTS 1 057 174 people who tested positive for SARS-CoV-2 between 1 February 2020 and 25 May 2021 in Sweden, matched on age, sex, and county of residence to 4 076 342 control participants. MAIN OUTCOMES MEASURES Self-controlled case series and conditional Poisson regression were used to determine the incidence rate ratio and risk ratio with corresponding 95% confidence intervals for a first deep vein thrombosis, pulmonary embolism, or bleeding event. In the self-controlled case series, the incidence rate ratios for first time outcomes after covid-19 were determined using set time intervals and the spline model. The risk ratios for first time and all events were determined during days 1-30 after covid-19 or index date using the matched cohort study, and adjusting for potential confounders (comorbidities, cancer, surgery, long term anticoagulation treatment, previous venous thromboembolism, or previous bleeding event). RESULTS Compared with the control period, incidence rate ratios were significantly increased 70 days after covid-19 for deep vein thrombosis, 110 days for pulmonary embolism, and 60 days for bleeding. In particular, incidence rate ratios for a first pulmonary embolism were 36.17 (95% confidence interval 31.55 to 41.47) during the first week after covid-19 and 46.40 (40.61 to 53.02) during the second week. Incidence rate ratios during days 1-30 after covid-19 were 5.90 (5.12 to 6.80) for deep vein thrombosis, 31.59 (27.99 to 35.63) for pulmonary embolism, and 2.48 (2.30 to 2.68) for bleeding. Similarly, the risk ratios during days 1-30 after covid-19 were 4.98 (4.96 to 5.01) for deep vein thrombosis, 33.05 (32.8 to 33.3) for pulmonary embolism, and 1.88 (1.71 to 2.07) for bleeding, after adjusting for the effect of potential confounders. The rate ratios were highest in patients with critical covid-19 and highest during the first pandemic wave in Sweden compared with the second and third waves. In the same period, the absolute risk among patients with covid-19 was 0.039% (401 events) for deep vein thrombosis, 0.17% (1761 events) for pulmonary embolism, and 0.101% (1002 events) for bleeding. CONCLUSIONS The findings of this study suggest that covid-19 is a risk factor for deep vein thrombosis, pulmonary embolism, and bleeding. These results could impact recommendations on diagnostic and prophylactic strategies against venous thromboembolism after covid-19.Peer reviewe

Antipsychotic drugs and risks of myocardial infarction: a self-controlled case series study.

AIM: Antipsychotics increase the risk of stroke. Their effect on myocardial infarction remains uncertain because people prescribed and not prescribed antipsychotic drugs differ in their underlying vascular risk making between-person comparisons difficult to interpret. The aim of our study was to investigate this association using the self-controlled case series design that eliminates between-person confounding effects. METHODS AND RESULTS: All the patients with a first recorded myocardial infarction and prescription for an antipsychotic identified in the Clinical Practice Research Datalink linked to the Myocardial Ischaemia National Audit Project were selected for the self-controlled case series. The incidence ratio of myocardial infarction during risk periods following the initiation of antipsychotic use relative to unexposed periods was estimated within individuals. A classical case-control study was undertaken for comparative purposes comparing antipsychotic exposure among cases and matched controls. We identified 1546 exposed cases for the self-controlled case series and found evidence of an association during the first 30 days after the first prescription of an antipsychotic, for first-generation agents [incidence rate ratio (IRR) 2.82, 95% confidence interval (CI) 2.0-3.99] and second-generation agents (IRR: 2.5, 95% CI: 1.18-5.32). Similar results were found for the case-control study for new users of first- (OR: 3.19, 95% CI: 1.9-5.37) and second-generation agents (OR: 2.55, 95% CI: 0.93-7.01) within 30 days of their myocardial infarction. CONCLUSION: We found an increased risk of myocardial infarction in the period following the initiation of antipsychotics that was not attributable to differences between people prescribed and not prescribed antipsychotics

Detection of Infectious Disease Outbreaks From Laboratory Data With Reporting Delays

Many statistical surveillance systems for the timely detection of outbreaks of infectious disease operate on laboratory data. Such data typically incur reporting delays between the time at which a specimen is collected for diagnostic purposes, and the time at which the results of the laboratory analysis become available. Statistical surveillance systems currently in use usually make some ad hoc adjustment for such delays, or use counts by time of report. We propose a new statistical approach that takes account of the delays explicitly, by monitoring the number of specimens identified in the current and past m time units, where m is a tuning parameter. Values expected in the absence of an outbreak are estimated from counts observed in recent years (typically 5 years). We study the method in the context of an outbreak detection system used in the United Kingdom and several other European countries. We propose a suitable test statistic for the null hypothesis that no outbreak is currently occurring. We derive its null variance, incorporating uncertainty about the estimated delay distribution. Simulations and applications to some test datasets suggest the method works well, and can improve performance over ad hoc methods in current use. Supplementary materials for this article are available online

Comparison of Statistical Algorithms for the Detection of Infectious Disease Outbreaks in Large Multiple Surveillance Systems

A large-scale multiple surveillance system for infectious disease outbreaks has been in operation in England and Wales since the early 1990s. Changes to the statistical algorithm at the heart of the system were proposed and the purpose of this paper is to compare two new algorithms with the original algorithm. Test data to evaluate performance are created from weekly counts of the number of cases of each of more than 2000 diseases over a twenty-year period. The time series of each disease is separated into one series giving the baseline (background) disease incidence and a second series giving disease outbreaks. One series is shifted forward by twelve months and the two are then recombined, giving a realistic series in which it is known where outbreaks have been added. The metrics used to evaluate performance include a scoring rule that appropriately balances sensitivity against specificity and is sensitive to variation in probabilities near 1. In the context of disease surveillance, a scoring rule can be adapted to reflect the size of outbreaks and this was done. Results indicate that the two new algorithms are comparable to each other and better than the algorithm they were designed to replace

A modified self‐controlled case series method for event‐dependent exposures and high event‐related mortality, with application to COVID‐19 vaccine safety

We propose a modified self‐controlled case series (SCCS) method to handle both event‐dependent exposures and high event‐related mortality. This development is motivated by an epidemiological study undertaken in France to quantify potential risks of cardiovascular events associated with COVID‐19 vaccines. Event‐dependence of vaccinations, and high event‐related mortality, are likely to arise in other SCCS studies of COVID‐19 vaccine safety. Using this case study and simulations to broaden its scope, we explore these features and the biases they may generate, implement the modified SCCS model, illustrate some of the properties of this model, and develop a new test for presence of a dose effect. The model we propose has wider application, notably when the event of interest is death

Risk of Injection-Site Abscess among Infants Receiving a Preservative-Free, Two-Dose Vial Formulation of Pneumococcal Conjugate Vaccine in Kenya.

There is a theoretical risk of adverse events following immunization with a preservative-free, 2-dose vial formulation of 10-valent-pneumococcal conjugate vaccine (PCV10). We set out to measure this risk. Four population-based surveillance sites in Kenya (total annual birth cohort of 11,500 infants) were used to conduct a 2-year post-introduction vaccine safety study of PCV10. Injection-site abscesses occurring within 7 days following vaccine administration were clinically diagnosed in all study sites (passive facility-based surveillance) and, also, detected by caregiver-reported symptoms of swelling plus discharge in two sites (active household-based surveillance). Abscess risk was expressed as the number of abscesses per 100,000 injections and was compared for the second vs first vial dose of PCV10 and for PCV10 vs pentavalent vaccine (comparator). A total of 58,288 PCV10 injections were recorded, including 24,054 and 19,702 identified as first and second vial doses, respectively (14,532 unknown vial dose). The risk ratio for abscess following injection with the second (41 per 100,000) vs first (33 per 100,000) vial dose of PCV10 was 1.22 (95% confidence interval [CI] 0.37-4.06). The comparator vaccine was changed from a 2-dose to 10-dose presentation midway through the study. The matched odds ratios for abscess following PCV10 were 1.00 (95% CI 0.12-8.56) and 0.27 (95% CI 0.14-0.54) when compared to the 2-dose and 10-dose pentavalent vaccine presentations, respectively. In Kenya immunization with PCV10 was not associated with an increased risk of injection site abscess, providing confidence that the vaccine may be safely used in Africa. The relatively higher risk of abscess following the 10-dose presentation of pentavalent vaccine merits further study