Self-controlled Case Series Method Research Articles

Sirolimus Can Increase the Disappearance Rate of Cardiac Rhabdomyomas Associated with Tuberous Sclerosis: A Prospective Cohort and Self-Controlled Case Series Study

To investigate the efficacy and safety of sirolimus in the treatment of cardiac rhabdomyomas associated with tuberous sclerosis complex and the specific benefits in different subgroups. The study was a prospective cohort and self-controlled case series study. Based on the prevalence of cardiac rhabdomyoma at different ages, we estimated the natural tumor disappearance rate. The subgroup analysis was done by Cox regression. Self-controlled case series method was used to assess the magnitude and duration of the drug effect. Adverse events were described. A total of 217 patients were included in the cohort study. Tumor disappearance rate was higher in younger age groups (hazard ratio = 0.99, P=.027) and female patients (hazard ratio=2.08, P=.015). The age-adjusted incidence ratio showed that the disappearance of rhabdomyomas between 3 and 6months was more related to sirolimus. Adverse events were observed 60 times in 42 of 217 children, mainly stomatitis. Sirolimus can increase the disappearance rate of cardiac rhabdomyoma in the tuberous sclerosis complex population. Efficacy varies by sex and age: female and younger patients have higher tumor disappearance rate. Sirolimus is well-tolerated.

Assessing the impact of preventive mass vaccination campaigns on yellow fever outbreaks in Africa: A population-level self-controlled case series study.

The Eliminate Yellow fever Epidemics (EYE) strategy was launched in 2017 in response to the resurgence of yellow fever in Africa and the Americas. The strategy relies on several vaccination activities, including preventive mass vaccination campaigns (PMVCs). However, to what extent PMVCs are associated with a decreased risk of outbreak has not yet been quantified. We used the self-controlled case series (SCCS) method to assess the association between the occurrence of yellow fever outbreaks and the implementation of PMVCs at the province level in the African endemic region. As all time-invariant confounders are implicitly controlled for in the SCCS method, this method is an alternative to classical cohort or case-control study designs when the risk of residual confounding is high, in particular confounding by indication. The locations and dates of outbreaks were identified from international epidemiological records, and information on PMVCs was provided by coordinators of vaccination activities and international funders. The study sample consisted of provinces that were both affected by an outbreak and targeted for a PMVC between 2005 and 2018. We compared the incidence of outbreaks before and after the implementation of a PMVC. The sensitivity of our estimates to a range of assumptions was explored, and the results of the SCCS method were compared to those obtained through a retrospective cohort study design. We further derived the number of yellow fever outbreaks that have been prevented by PMVCs. The study sample consisted of 33 provinces from 11 African countries. Among these, the first outbreak occurred during the pre-PMVC period in 26 (79%) provinces, and during the post-PMVC period in 7 (21%) provinces. At the province level, the post-PMVC period was associated with an 86% reduction (95% CI 66% to 94%, p < 0.001) in the risk of outbreak as compared to the pre-PMVC period. This negative association between exposure to PMVCs and outbreak was robustly observed across a range of sensitivity analyses, especially when using quantitative estimates of vaccination coverage as an alternative exposure measure, or when varying the observation period. In contrast, the results of the cohort-style analyses were highly sensitive to the choice of covariates included in the model. Based on the SCCS results, we estimated that PMVCs were associated with a 34% (95% CI 22% to 45%) reduction in the number of outbreaks in Africa from 2005 to 2018. A limitation of our study is the fact that it does not account for potential time-varying confounders, such as changing environmental drivers of yellow fever and possibly improved disease surveillance. In this study, we provide new empirical evidence of the high preventive impact of PMVCs on yellow fever outbreaks. This study illustrates that the SCCS method can be advantageously applied at the population level in order to evaluate a public health intervention.

Risk of intussusception after monovalent rotavirus vaccine (Rotavac) in Indian infants: A self-controlled case series analysis

BackgroundAn association between rotavirus vaccination and intussusception has been documented in post-licensure studies in some countries. We evaluated the risk of intussusception associated with monovalent rotavirus vaccine (Rotavac) administered at 6, 10 and 14 weeks of age in India. MethodsActive prospective surveillance for intussusception was conducted at 22 hospitals across 16 states from April 2016 through September 2017. Data on demography, clinical features and vaccination were documented. Age-adjusted relative incidence for 1–7, 8–21, and 1–21 days after rotavirus vaccination in children aged 28–364 days at intussusception onset was estimated using the self-controlled case-series (SCCS) method. Only Brighton Collaboration level 1 cases were included. ResultsOut of 670 children aged 2–23 months with intussusception, 311 (46.4%) children were aged 28–364 days with confirmed vaccination status. Out of these, 52 intussusception cases with confirmed receipt of RVV were included in the SCCS analysis. No intussusception case was observed within 21 days of dose 1. Only one case occurred during 8–21 days after the dose 2. Post-dose 3, two cases in 1–7 days and 7 cases during 8–21 days period were observed. There was no increased risk of intussusception during 1–7 days after the doses 1 and 2 (zero cases observed) or dose 3 (relative incidence [RI], 1.71 [95% confidence interval {CI} 0.0–5.11]). Similarly, no increased risk during 8–21 days after the dose 1 (zero cases observed), dose 2 (RI, 0.71 [95% CI, 0.0–3.28]) or dose 3 (RI, 2.52 [95% CI, 0.78–5.61]). The results were similar for 1–21 day periods after the doses separately or pooled. ConclusionsThe risk of intussusception during the first 21 days after any dose of rotavirus vaccine (Rotavac) was not higher among the Indian infants than the background risk, based on limited SCCS analysis of 52 children.

Incidence and seasonality of type 1 diabetes: a population-based 3-year cohort study using the National Database in Japan.

IntroductionTo investigate the incidence of type 1 diabetes by age group (0–19, 20–39, 40–59, ≥60 years) in Japan and whether there is seasonality in this incidence.Research design and methodsThe incidence of type 1 diabetes from September 2014 to August 2017 was estimated using 2013–2018 data from the National Database of Health Insurance Claims and Specific Health Check-ups of Japan. The incidence rate was analyzed using Tango’s Index and the self-controlled case series method.ResultsOverall, 10 400 of the 79 175 553 included individuals were diagnosed with type 1 diabetes. The incidence of type 1 diabetes from September 2014 to August 2017 was 4.42/100 000 person-years. The incidence rates for men aged 0–19, 20–39, 40–59, and ≥60 years were 3.94, 5.57, 5.70, and 3.48, respectively. Among women, the incidence rates for the same age ranges were 5.22, 4.83, 4.99, and 3.31, respectively. Tango’s index showed that the incidence rate of type 1 diabetes was significantly associated with seasons among those aged 0–19 years. Further, the self-controlled case series method showed a significant interaction between age and season, with the incidence of type 1 diabetes being higher in spring for patients younger than 20 years of age.ConclusionsIn Japan, men aged 40–59 years and women aged 0–19 years are the groups with the highest incidence of type 1 diabetes. Further, the incidence of younger-onset diabetes in Japan was higher in spring (from March to May).

Assessment of risk of intussusception after pilot rollout of rotavirus vaccine in the Indian public health system

BackgroundPre-licensure trials of ROTAVAC® were not adequately powered to assess risk of intussusception, a rare adverse event associated with other rotavirus vaccines in some settings. We examined the risk of intussusception after ROTAVAC® vaccination among Indian infants during pilot rollout of the vaccine in the public health system in three states - Himachal Pradesh, Maharashtra and Tamil Nadu. MethodsPassive surveillance for intussusception was set up in 35 sentinel health facilities covering 26.3 million population in the three states under monitoring of an Interministerial-Interagency Steering Committee. Clinical and immunization data were collected by independent teams. An expert committee blinded to vaccination status, classified intussusception cases using Brighton criteria. The self-controlled case-series method was used to estimate risk of intussusception (Brighton Level 1) after ROTAVAC® vaccination. Results151 intussusception cases were included in the analysis. The relative incidence (incidence during the risk period compared to the control period) 1–21 days after doses 1 and 2 combined was 1.56 (95% CI, 0.0–5.28) and that for three doses combined was 1.88 (95% CI, 0.76–4.30). Attributable risk 1–21 days after doses 1 and 2 combined was 0.11 (95% CI, 0.0–0.25) and that for 3 doses combined was 0.42 (95% CI, 0.0–0.70) per 100,000 doses. ConclusionsNo increased risk of intussusception within 21 days of receipt of the first two doses combined or all 3 doses combined of ROTAVAC® was detected.

The risk of Kawasaki disease after pneumococcal conjugate & meningococcal B vaccine in England: A self-controlled case-series analysis

Kawasaki disease (KD) is an uncommon condition occasionally reported after childhood vaccination. Admissions with a KD-compatible diagnosis identified from a national database in England were linked to immunisation records to investigate the risk after pneumococcal conjugate (PCV) or meningococcal B (MenB) vaccines. Both are given at 2/4/12 months of age but were introduced sequentially, allowing their effects to be separately assessed. A total of 553 linked admissions in 512 individuals were validated as KD. The relative incidence (RI) within 28 days of PCV doses 1 or 2 measured by the self-controlled case-series method was 0.62 (95% confidence interval (CI) 0.38–1.00) with a significantly decreased risk after dose 3 (RI 0.30 (95% CI 0.11–0.77)). For MenB vaccine, the RI after doses 1 or 2 was 1.03 (95% CI 0.51–2.05) and 0.64 (95% CI 0.08–5.26) after dose 3. This study shows no evidence of an increased risk of KD after either vaccine.

Safety of live attenuated herpes zoster vaccine in adults 70–79 years: A self-controlled case series analysis using primary care data from Australia’s MedicineInsight program

BackgroundAustralia introduced a funded shingles vaccination program for older adults in November 2016, administered predominantly in primary care clinics. MedicineInsight, a nationally representative primary care database, was used to investigate the risk of pre-specified outcomes following live attenuated herpes zoster vaccine (ZVL) in Australia. MethodsIndividuals aged 70–79 years who received ZVL between 1 November 2016 and 31 July 2018 were identified from MedicineInsight. The self-controlled case series (SCCS) method was used to estimate the seasonally-adjusted relative incidence (RI) of seven pre-specified outcome events (injection site reaction (ISR) [positive control], burn [negative control], myocardial infarction (MI), stroke, rash, rash with an antiviral prescription, and clinical attendance) during a plausible post-vaccination at-risk window compared with times distant from vaccination. Sensitivity analyses examined the effect of common concomitant vaccinations and restriction to first outcome events. ResultsA total of 332,988 vaccination encounters among 150,054 individuals were identified during the study period; over 2 million clinical attendances were observed. There was an increased RI of ISR in the seven days following ZVL (RI = 77.4, 95% CI 48.1–124.6); the RI of clinical attendance (RI = 0.94, 95% CI 0.94–0.95) and stroke (RI = 0.58, 95% CI 0.44–0.78) were lower in the 42 days following administration of ZVL compared to control periods. There was no evidence of a change in the RI of MI (RI = 0.74, 95% CI 0.41–1.33), rash (RI = 0.97, 95% CI 0.88–1.08), or rash with antiviral prescription (RI = 0.83, 95% CI 0.62–1.10) in the 42 days following ZVL compared to control periods. ConclusionNo new safety concerns were identified for ZVL in this study based on a novel, Australian primary care data source. An expected increased risk of ISR was identified; findings in relation to cardiovascular disease were reassuring but require confirmation using additional data, including hospital records.

ADVANCE system testing: Estimating the incidence of adverse events following pertussis vaccination in healthcare databases with incomplete exposure data

The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public–private collaboration aiming to develop and test a system for rapid vaccine benefit-risk monitoring using existing European healthcare databases. Incidence rate (IR) estimates of vaccination-associated adverse events that are needed to model vaccination risks can be calculated from existing healthcare databases when vaccination (exposure) data are available. We assessed different methods to derive IRs in risk periods following vaccination when exposure data are missing in one database, using estimated IRs and IRRs from other databases for febrile seizures, fever and persistent crying. IRs were estimated for children aged 0–5 years in outcome-specific risk and non-risk periods following the first dose of acellular pertussis (aP) vaccination in four primary care databases and one hospital database. We compared derived and observed IRs in each database using three methods: 1) multiplication of non-risk period IR for database i by IR ratio (IRR) obtained from meta-analysis of IRRs estimated using the self-controlled case-series method, from databases other than i; 2) same method as 1, but multiplying with background IR; and 3) meta-analyses of observed IRs from databases other than i. IRs for febrile seizures were lower in primary care databases than the hospital database. The derived IR for febrile seizures using data from primary care databases was lower than that observed in the hospital database, and using data from the hospital database gave a higher derived IR than that observed in the primary care database. For fever and persistent crying the opposite was observed. We demonstrated that missing IRs for a post-vaccination period can be derived but that the type of database and the method of event data capture can have an impact on potential bias. We recommend IRs are derived using data from similar database types (hospital or primary care) with caution as even this can give heterogeneous results.

Seasonal influenza vaccine and Guillain-Barré syndrome: A self-controlled case series study.

To evaluate the risk of Guillain-Barré syndrome (GBS) following seasonal influenza vaccination based on French nationwide data. All cases of GBS occurring in metropolitan France between September 1 and March 31 from 2010 to 2014 were identified from the French national health data system. Data were analyzed according to the self-controlled case series method. The risk period started 1 day after the patient received vaccine (D1) until 42 days after vaccination (D42). The incidence of GBS during this risk period was compared to that of the control period (D43-March 31). The incidence rate ratio (IRR) was estimated after adjusting for seasonality and presence or not of acute infections. Between September and March, of the 2010/2011 to 2013/2014 influenza vaccination seasons, 3,523 cases of GBS occurred in metropolitan France and were included in the study. Among them, 15% (527 patients) had received influenza vaccination. A total of 140 patients developed GBS during the 42 days following influenza vaccination. The crude risk of developing GBS was not significantly increased during the 42 days following influenza vaccination (IRR, 1.02; 95% confidence interval [CI], 0.83-1.25; p = 0.85). This result remained nonsignificant after adjustment for calendar months and the incidence of acute gastrointestinal and respiratory tract infections (IRR, 1.10; 95% CI, 0.89-1.37; p = 0.38). In contrast, the risk of GBS was fourfold higher after acute respiratory tract infection (IRR, 3.89; 95% CI, 3.52-4.30; p < 0.0001) or gastrointestinal infection (IRR, 3.64; 95% CI, 3.01-4.40; p < 0.0001). No association between seasonal influenza vaccination and GBS was shown during the 42 days following vaccination.

Bayesian Analysis of Zero-Truncated Poisson Model: Application to the Self-Controlled Case-series Design

A Bayesian Self-Controlled Case-Series (BSCCS) method is proposed and used to estimate the relative risk of an adverse drug event (ADE) given transient exposure to a drug or vaccine. Markov Chain Monte Carlo (MCMC) methods through WinBUGS are used to estimate parameters of the model given different settings and sample sizes. The method explores full posterior distribution for the model to obtain the relative risk estimates which at times is a challenge in likelihood analysis of complex models. Data was simulated for 10, 20 or 50 children aged between 365 and 730 days, and received their first dose of the measles, mumps, and rubella (MMR) vaccine within this follow-up period. Each child had the outcome event – viral-meningitis, in the follow-up period. Results of the data analysis indicated an increased risk of viral meningitis within 14-35 days post vaccination. Results of Bayesian approach are quite similar to the MLE risk estimates, assuming a non-informative prior. However, with more informative priors, BSCCS method produced better results with narrow credible intervals. For the real data, children aged 365 and 730 days, exposed to MMR vaccine, with viral meningitis (single exposure) were considered. While the frequentist approach estimated the incidence rate ratio (IRR) as IRR 12.037 (95% CI (3.002 - 48.259)), the Bayesian estimate was IRR 8.971 (95% CI 2.869 - 27.994). This is similar to the MLE results but with narrow credible intervals. In all cases, there is significantly higher risk of viral meningitis within 14-35 days post MMR vaccination. Results from the simulation study and real data revealed that the BSCCS model fitted better than the SCCS model.

Hospitalization following influenza infection and pandemic vaccination in multiple sclerosis patients: a nationwide population-based registry study from Norway.

Patients with multiple sclerosis (MS) are at increased risk of infections and related worsening of neurological function. Influenza infection has been associated with increased risk of various neurological complications. We conducted a population-based registry study to investigate the risk of acute hospitalization of MS patients in relation to influenza infection or pandemic vaccination in Norway. The entire Norwegian population in the years 2008–2014 was defined as our study population (N = 5,219,296). Information on MS diagnosis, influenza infection and vaccination were provided by Norwegian national registries. The self-controlled case series method was used to estimate incidence rate ratios (IRRs) with 95% confidence intervals (95% CI) in defined risk periods. 6755 MS patients were identified during the study period. Average age at first registration of an MS diagnosis was 51.8 years among men and 49.9 years among females (66.9%). The IRR for emergency hospitalization among MS patients the first week after an influenza diagnosis was 3.4 (95% CI 2.4–4.8). The IRR was 5.6 (95% CI 2.7–11.3) after pandemic influenza, and 4.8 (95% CI 3.1–7.4) after seasonal influenza. Pandemic vaccination did not influence risk of hospitalization [IRR within the first week: 0.7 (95% CI 0.5–1.0)]. Among MS patients, influenza infection was associated with increased risk for acute hospitalization while no increased risk was observed after pandemic vaccination. Influenza vaccination could prevent worsening of MS-related symptoms as well as risk of hospitalization.

Do Vaccines Trigger Neurological Diseases? Epidemiological Evaluation of Vaccination and Neurological Diseases Using Examples of Multiple Sclerosis, Guillain-Barré Syndrome and Narcolepsy.

This article evaluates the epidemiological evidence for a relationship between vaccination and neurological disease, specifically multiple sclerosis, Guillain–Barré syndrome and narcolepsy. The statistical methods used to test vaccine safety hypotheses are described and the merits of different study designs evaluated; these include the cohort, case-control, case-coverage and the self-controlled case-series methods. For multiple sclerosis, the evidence does not support the hypothesized relationship with hepatitis B vaccine. For Guillain−Barré syndrome, the evidence suggests a small elevated risk after influenza vaccines, though considerably lower than after natural influenza infection, with no elevated risk after human papilloma virus vaccine. For narcolepsy, there is strong evidence of a causal association with one adjuvanted vaccine used in the 2009/10 influenza pandemic. Rapid investigation of vaccine safety concerns, however biologically implausible, is essential to maintain public and professional confidence in vaccination programmes.

The risk of non-specific hospitalised infections following MMR vaccination given with and without inactivated vaccines in the second year of life. Comparative self–controlled case-series study in England

Observational cohort studies in high-income settings have suggested that vaccination order may affect children’s subsequent risk of a heterologous infection, with live vaccines reducing and inactivated vaccines (given on their own or with a live vaccine), increasing the risk. We used the self-controlled case-series method, which automatically controls for the individual level confounding to which such cohort studies are prone, to test this hypothesis. We compared the relative incidence (RI) of infections post-vaccination in two calendar periods in England; in Period 1 (September 2002–August 2006) live measles, mumps, rubella (MMR) vaccine was given on its own and in Period 2 (September 2006–April 2010) inactivated vaccines (7-valent pneumococcal conjugate vaccine (PCV7) and sometimes the combined Haemophilus influenzae type b/meningococcal group C vaccine (Hib-MenC)) were given concomitantly with MMR. Admissions for an infection of the upper or lower respiratory tract, gastrointestinal system or other site in children aged 11–23 months were selected from the Hospital Episode Statistics database in England and linked to child health immunisation histories. The analysis included a total of 24,144 infections in 21,067 children in Period 1 and 36,880 in 31,616 children in Period 2. The RI of admission for any infection in Period 1 was 1.00 (95% confidence interval 0.95–1.06) compared with 0.95 (95% confidence interval 0.90–1.00) in Period 2. Comparing the two periods showed no evidence of a difference in the relative incidence estimates with a ratio of RI of 0.94 (95% confidence interval 0.87–1.02), RIs within 90 days of vaccination were 0.94 (0.91–0.97) in Period 1 and 0.94 (0.91–0.97) in Period 2, consistent with a temporary healthy vaccinee effect. In conclusion, we found no evidence to support the hypothesis that there is a reduction in heterologous infections after MMR on its own or an increase after MMR given concomitantly with an inactivated vaccine.

Evaluation of Intussusception After Oral Monovalent Rotavirus Vaccination in South Africa.

BackgroundPostlicensure studies have shown an association between rotavirus vaccination and intussusception. We assessed the risk of intussusception associated with Rotarix (RV1) administration, at 6 and 14 weeks of age, in an upper-middle-income country, South Africa.MethodsActive prospective surveillance for intussusception was conducted in 8 hospitals from September 2013 through December 2017. Retrospective case enrollment was done at 1 hospital from July 2012 through August 2013. Demographic characteristics, symptom onset, and rotavirus vaccine status were ascertained. Using the self-controlled case-series method, we estimated age-adjusted incidence rate ratios within 1–7, 8–21, and 1–21 days of rotavirus vaccination in children aged 28–275 days at onset of symptoms. In addition, age-matched controls were enrolled for a subset of cases (n = 169), and a secondary analysis was performed.ResultsThree hundred forty-six cases were included in the case-series analysis. Post–dose 1, there were zero intussusception cases within 1–7 days, and 5 cases within 8–21 days of vaccination. Post–dose 2, 15 cases occurred within 1–7 days, and 18 cases within 8–21 days of vaccination. There was no increased risk of intussusception 1–7 days after dose 1 (no cases observed) or dose 2 (relative incidence [RI], 1.71 [95% confidence interval {CI} .83–3.01]). Similarly, there was no increased risk 8–21 days after the first (RI, 4.01 [95% CI, .87–10.56]) or second dose (RI, .96 [95% CI, .52–1.60]). Results were similar for the case-control analysis.ConclusionsThe risk of intussusception in the 21 days after the first or second dose of RV1 was not higher than the background risk among South Africa infants.Clinical Trials RegistrationSouth African National Clinical Trial Register (DOH-27-0913-4183).

Self-Controlled Case Series Methodology

The self-controlled case series method is an epidemiological study design in which individuals act as their own control. The method offers advantages but has several limitations. This article outlines the self-controlled case series method and reviews methodological developments that address some of these limitations.

Association of Risk of Incident and Recurrent Venous Thromboembolism with Oral Glucocorticoid Treatment

Glucocorticoids are potent anti-inflammatory drugs used for a variety of chronic diseases and acute conditions that, unfortunately, can also cause severe adverse events. Venous thromboembolism (VTE) has recently been added to the list of clinical complications associated with glucocorticoids. Epidemiological studies reported that the risk for first VTE is increased by 2 to 3-fold with the use of glucocorticoids. However, several confounders may account for the reported association and whether glucocorticoid use increases the risk of recurrent VTE is unknown. To address the issue of confounding, we determined the frequency of a first VTE event associated with the use of oral glucocorticoids employing the self-controlled case-series (SCCS) method. With SCCS every individual is contrasted with him or herself thereby eliminating fixed confounders such as age, sex or chronic comorbidity. In addition, we evaluated the effect of oral glucocorticoids on the risk of recurrent VTE in a cohort design.Patients with VTE from the MEGA study were individually linked to the Dutch Foundation for Pharmaceutical Statistics (SFK). Prescriptions of oral glucocorticoids in the period of the MEGA study were identified. The risk for the first VTE was estimated using SCCS method and conditional Poisson regression. The association between oral glucocorticoids and recurrent VTE was examined using age and sex adjusted Cox regression models.A total of 2547 patients could be linked to the SFK data register, from those 363 received at least one outpatient prescription of oral glucocorticoids. The risk for a first VTE event was 3.5-fold higher in the aggregated period of oral glucocorticoid treatment as compared with baseline periods (incident rate ratio [IRR] 3.5, 95% confidence interval [CI] 2.6-4.8). IRR of a first VTE event was 2.5 (95% CI, 1.1- 5.7) in the week before treatment started, 5.3 (95% CI, 2.9 - 9.5) during the first 7 days with treatment, 3.7 (95% CI, 2.6 - 5.2) until six months with treatment and 1.6 (95% CI, 0.8 - 3.1) after 6 months with oral glucocorticoids, as compared with the baseline period. A dose-dependent relationship between oral glucocorticoid treatment and VTE risk was observed as the IRR increased from 3.4 (95% CI, 2.3 - 5.0) with 30-day cumulative doses below 300mg to 4.9 (95% CI, 1.7 - 14.0) with 30-day cumulative doses above 2000mg, as compared with baseline periods. IRRs for DVT (3.9; 95% CI, 2.9 - 9.5) and PE (3.1; 95% CI, 2.0 - 4.9) were similar and IRR for unprovoked VTE (2.4; 95% CI, 1.3 - 4.7) was lower than the IRR for provoked VTE (4.2; 95% CI, 2.9 - 6.0). The rates of recurrent VTE were elevated in patients with unprovoked VTE and in those who had their first VTE during a period of oral glucocorticoid treatment, either if the first event was otherwise classified as provoked or unprovoked. The adjusted HR for recurrent VTE was 1.6 (95% CI, 1.2 - 2.0) in patients with unprovoked first VTE not using oral glucocorticoids at the time of their first event, 2.1 (95% CI, 1.2 - 3.8) in those who had a provoked first VTE while using oral glucocorticoids and 2.3 (95% CI, 1.2 - 7.0) in those with an unprovoked first VTE while using the drug, as compared with patients with a provoked first event not using oral glucocorticoids at the time of their first event. The risk for recurrent VTE was 2.7-fold increased (95% CI, 1.6 - 4.8) during glucocorticoid treatment periods as compared to baseline periods.We conclude that patients receiving oral glucocorticoids had an approximately three-fold increase in the risk for first and recurrent VTE. The observed risk for VTE was partly associated with the underlying disease (preexposure period) and increased further after oral glucocorticoids were prescribed. These results underscore that treatment strategies to prevent first and recurrent VTE in patients treated with oral glucocorticoids are needed. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Self-controlled case series studies: Just how rare does a rare non-recurrent outcome need to be?

The self-controlled case series method assumes that adverse outcomes arise according to a non-homogeneous Poisson process. This implies that it is applicable to independent recurrent outcomes. However, the self-controlled case series method may also be applied to unique, non-recurrent outcomes or first outcomes only, in the limit where these become rare. We investigate this rare outcome assumption when the self-controlled case series method is applied to non-recurrent outcomes. We study this requirement analytically and by simulation, and quantify what is meant by 'rare' in this context. In simulations we also apply the self-controlled risk interval design, a special case of the self-controlled case series design. To illustrate, we extract data on the incidence rate of some recurrent and non-recurrent outcomes within a defined study population to check whether outcomes are sufficiently rare for the rare outcome assumption to hold when applying the self-controlled case series method to first or unique outcomes. The main findings are that the relative bias should be no more than 5% when the cumulative incidence over total time observed is less than 0.1 per individual. Inclusion of age (or calendar time) effects will further reduce bias. Designs that begin observation with exposure maximise bias, whereas little or no bias will be apparent when there is no time trend in the distribution of exposures, or when exposure is central within time observed.

Quadrivalent human papillomavirus vaccination in girls and the risk of autoimmune disorders: the Ontario Grade 8 HPV Vaccine Cohort Study.

Despite demonstrated effectiveness in real-world settings, concerns persist regarding the safety of the quadrivalent human papillomavirus (HPV4) vaccine. We sought to assess the risk of autoimmune disorders following HPV4 vaccination among grade 8 girls eligible for Ontario's school-based HPV vaccination program. We undertook a population-based retrospective cohort study using Ontario's administrative health and vaccination databases from 2007 to 2013. The self-controlled case series method was used to compare the rate of a composite end point of autoimmune disorders diagnosed during days 7-60 post-vaccination ("exposed" follow-up) to that at any other time ("unexposed"). The analysis was repeated to assess the effect of a history of immune-mediated diseases and time since vaccination. We also conducted an exploratory analysis of individual autoimmune disorders. Rate ratios and 95% confidence intervals (CIs) were estimated using conditional Poisson regression, adjusted for age, seasonality, concomitant vaccinations and infections. The study cohort consisted of 290 939 girls aged 12-17 years who were eligible for vaccination between 2007 and 2013. There was no significant risk for developing an autoimmune disorder following HPV4 vaccination (n = 681; rate ratio 1.12, 95% CI 0.85-1.47), and the association was unchanged by a history of immune-mediated disorders and time since vaccination. Exploratory analyses of individual autoimmune disorders found no significant risks, including for Bell palsy (n = 65; rate ratio 1.73, 95% CI 0.77-3.89), optic neuritis (n = 67; rate ratio 1.57, 95% CI 0.74-3.33) and Graves disease (n = 47; rate ratio 1.55, 95% CI 0.92-2.63). We did not observe an increased risk of autoimmune disorders following HPV4 vaccination among teenaged girls. These findings should reassure parents and health care providers.

Acetaminophen administration and the risk of acute kidney injury: a self-controlled case series study.

BackgroundAcetaminophen (APAP) is frequently used for analgesia and is considered safer than nonsteroidal anti-inflammatory drugs (NSAIDs) for the kidneys. However, there is little epidemiological evidence of the association between APAP and acute kidney injury (AKI).ObjectivesTo examine the association between APAP and AKI using the self-controlled case series (SCCS) method, which is a novel strategy to control between-person confounders by comparing the risk and reference periods in each patient.MethodsWe performed SCCS in 1,871 patients (39.9% female) who were administered APAP and subsequently developed AKI, by reviewing electronically stored hospital information system data from May 2011 to July 2016. We used conditional Poisson regression to compare each patient’s risk and reference period. As a time-varying confounder, we adjusted the status of liver and kidney functions, systemic inflammation, and exposure to NSAIDs.ResultsWe identified 5,650 AKI events during the 260,549 person-day observation period. The unadjusted incidences during the reference and exposure periods were 2.01/100 and 3.12/100 person-days, respectively. The incidence rate ratio adjusted with SCCS was 1.03 (95% confidence interval [CI]: 0.95–1.12). When we restricted endpoints as stage 2 AKI- and stage 3 AKI-level creatinine elevations, the incidence rate ratios were 1.20 (95% CI 0.91–1.58) and 1.20 (95% CI 0.62–2.31), respectively, neither of which was statistically significant.ConclusionOur findings added epidemiological information for the relationship between APAP administration and AKI development. The results indicated scarce association between APAP and AKI, presumably supporting the general physicians’ impression that APAP is safer for kidney.

Signal Detection for Recently Approved Products: Adapting and Evaluating Self-Controlled Case Series Method Using a US Claims and UK Electronic Medical Records Database.

The Self-Controlled Case Series (SCCS) method has been widely used for hypothesis testing, but there is limited evidence of its performance for safety signal detection. The objective of this study was to evaluate SCCS for signal detection on recently approved products. A retrospective study covered the period after three recently marketed drugs were launched through to 31 December 2010 using The Health Improvement Network, a UK primary care database, and Optum, a US claims database. The SCCS method was applied to examine five heterogenous outcomes with desvenlafaxine and escitalopram and six outcomes with adalimumab for Signals of Disproportional Recording (SDRs); a positive finding was determined to be when the lower bound of 95% Confidence Interval ofthe incidence rate ratio (IRR) estimate was> 1. Multiple design choices were tested and the trend in IRR estimates over calendar time for one drug event pair was examined. All six outcomes with adalimumab, three of five outcomes with desvenlafaxine, and four of five outcomes with escitalopram had SDRs. SCCS highlighted all acute events in the primary analysis but was less successful with slower-onset outcomes. Performance varied by risk period definition. Changes in IRR estimates over quarterly intervals for adalimumabwith herpes zoster showed marked higher SDR within 9months of drug launch. SCCS shows promise for signal detection: it may highlight known associations for recent marketed products and has potential for early signal identification. SCCS performance varied by design choice and the nature of both exposure and event pair. Future work is needed to determine how effective the approach is in prospective testing and determining the performance characteristics of the approach.