Self-controlled Case Series Method Research Articles

Antibiotic Exposure and Risk of Community-associated Clostridium difficile infection (CA-CDI): A Self-Controlled Case Series Analysis

BackgroundCA-CDI accounts for up to 50% of all CDIs. Case–control studies (CCS) have been used to estimate the odds ratio (OR) of CA-CDI associated with antibiotic exposure. These ORs demonstrate significant heterogeneity across studies. Unlike CCS, a self-controlled case series (SCCS) design can be used to control for all time-invariant confounders leading to less biased effect estimates.MethodsAdults (≥18 years) registered (N = 139,670) with the Barrie and Community Family Health Team (BCFHT) were included in the study. Cases were defined as any patient with an incident case of CA-CDI and ≥1 antibiotic exposure occurring between January 1, 2011 and December 31, 2016. The SCCS model was used to estimate the association between antibiotic exposure and CA-CDI. The SCCS model yields estimates of the relative incidence rate of CA-CDI in exposure periods relative to non-exposure periods within a case. Exposure periods were defined as starting two days after any antibiotic prescription and ending 60 days later. Multiple exposure periods and time-varying confounders due to calendar year were included in the final model. The relative incidence rate ratio (IRR) was estimated using conditional poisson regression analysis. Proton pump inhibitor (PPI) use was included as an effect modifier. Antibiotics were divided into high-risk (fluoroquinolone, clindamycin, and cephalosporin) and low-risk exposures. Research ethics approval was obtained from the BFCHT research ethics board.ResultsAmong 544 total CDI cases, N = 189 CA-CDI cases met the inclusion criteria. Any antibiotic exposure increases the risk by ≥2-fold, with no difference observed between high and low-risk groups (IRR=1.11, 95% CI 0.53–2.36) (Table 1).ConclusionAntibiotic exposure increases the risk of CA-CDI, with IRR estimates similar to those observed for healthcare-associated-CDI. This, along with the control of all time-invariant confounders by the SCCS method suggests a less biased effect estimate previously reported from CCS.Table 1 Variable IRR 95% Confidence Interval P-value Antibiotic Exposure GroupPPINoneYes0.80(0.62–1.03)0.09Low riskYes1.95(0.09–4.24)0.09High riskYes1.20(0.42–3.40)0.73OverallLow risk2.03(1.19–3.47)0.009High risk2.26(1.29–3.98)0.005Disclosures All authors: No reported disclosures.

Risk of venous thromboembolism following influenza vaccination in adults aged 50years and older in the Vaccine Safety Datalink.

Influenza-like illness and inflammation are known risk factors for venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). However, few studies have characterized the risk of VTE following influenza vaccination. We examined VTE risk after vaccination in adults 50years old and older within the Vaccine Safety Datalink (VSD). We used the self-controlled case series method to determine the risk of VTE among age-eligible adults who received influenza vaccine (with or without pandemic H1N1) and experienced a VTE during the months of September through December in 2007 through 2012. Presumptive VTE cases were identified among VSD participants using diagnostic codes, diagnostic tests, and oral anticoagulant prescription. Potential cases were validated by medical record review. The VTE incidence rate ratio was calculated among confirmed cases for the risk window 1 to 10days after vaccination relative to all other person-time from September through December. Of the 1,488 presumptive cases identified, 508 were reviewed, of which 492 (97%) were confirmed cases of VTE. The analysis included 396 incident, confirmed cases. Overall, there was no increased risk of VTE in the 1 to 10days after influenza vaccination (IRR=0.89, 95% CI 0.69-1.17) compared to the control period. Results were similar when all person-time was censored before vaccination. A post hoc analysis showed an increased risk among current tobacco smokers (IRR=2.57, 95% CI 1.06-6.23). No clustering of VTE was observed in the 1-42days after vaccination. Overall, there was no evidence that inactivated influenza vaccine was associated with VTE in adults ≥50years old. An increased risk was found among current smokers in a post hoc analysis. These findings are consistent with previous research and support the safety of annual vaccination in this population.

Risk of Venous Thromboembolism Following Hemorrhagic Fever With Renal Syndrome: A Self-controlled Case Series Study.

Bleeding is associated with viral hemorrhagic fevers; however, thromboembolic complications have received less attention. Hemorrhagic fever with renal syndrome (HFRS) is a mild viral hemorrhagic fever caused by Puumala hantavirus. We previously identified HFRS as a risk factor for myocardial infarction and stroke, but the risk for venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is unknown. Personal identity numbers from the Swedish HFRS database were cross-linked with the National Patient register to obtain information on all causes for hospitalization during 1964 to 2013. The self-controlled case series method was used to calculate the incidence rate ratio (IRR) for first VTE, DVT, and PE during 1998 to 2013. From 7244 HFRS patients, there were 146 with a first VTE of which 74 were DVT and 78 were PE, and 6 patients had both DVT and PE. The overall risk for a VTE was significantly higher during the first 2 weeks following HFRS onset, with an IRR of 64.3 (95% confidence interval [CI], 36.3-114). The corresponding risk for a DVT was 45.9 (95% CI, 18-117.1) and for PE, 76.8 (95% CI, 37.1-159). Sex interacted significantly with the association between HFRS and VTE, with females having a higher risk compared with males. A significantly increased risk for VTE was found in the time period following HFRS onset. It is important to keep this in mind and monitor HFRS patients, and possibly other viral hemorrhagic fever patients, for early symptoms of VTE.

Spline‐based self‐controlled case series method

The self-controlled case series (SCCS) method is an alternative to study designs such as cohort and case control methods and is used to investigate potential associations between the timing of vaccine or other drug exposures and adverse events. It requires information only on cases, individuals who have experienced the adverse event at least once, and automatically controls all fixed confounding variables that could modify the true association between exposure and adverse event. Time-varying confounders such as age, on the other hand, are not automatically controlled and must be allowed for explicitly. The original SCCS method used step functions to represent risk periods (windows of exposed time) and age effects. Hence, exposure risk periods and/or age groups have to be prespecified a priori, but a poor choice of group boundaries may lead to biased estimates. In this paper, we propose a nonparametric SCCS method in which both age and exposure effects are represented by spline functions at the same time. To avoid a numerical integration of the product of these two spline functions in the likelihood function of the SCCS method, we defined the first, second, and third integrals of I-splines based on the definition of integrals of M-splines. Simulation studies showed that the new method performs well. This new method is applied to data on pediatric vaccines. Copyright © 2017 John Wiley & Sons, Ltd.

Effects of extreme temperatures on cardiovascular emergency hospitalizations in a Mediterranean region: a self-controlled case series study

BackgroundCold spells and heatwaves increase mortality. However little is known about the effect of heatwaves or cold spells on cardiovascular morbidity. This study aims to assess the effect of cold spells and heatwaves on cardiovascular diseases in a Mediterranean region (Catalonia, Southern Europe).MethodsWe conducted a population-based retrospective study. Data were obtained from the System for the Development of Research in Primary Care and from the Catalan Meteorological Service. The outcome was first emergency hospitalizations due to coronary heart disease, stroke, or heart failure. Exposures were: cold spells; cold spells and 3 or 7 subsequent days; and heatwaves. Incidence rate ratios (IRR) and 95% confidence intervals were calculated using the self-controlled case series method. We accounted for age, time trends, and air pollutants; results were shown by age groups, gender or cardiovascular event type.ResultsThere were 22,611 cardiovascular hospitalizations in winter and 17,017 in summer between 2006 and 2013. The overall incidence of cardiovascular hospitalizations significantly increased during cold spells (IRR = 1.120; CI 95%: 1.10–1.30) and the effect was even stronger in the 7 days subsequent to the cold spell (IRR = 1.29; CI 95%: 1.22–1.36). Conversely, cardiovascular hospitalizations did not increase during heatwaves, neither in the overall nor in the stratified analysis.ConclusionsCold spells but not heatwaves, increased the incidence of emergency cardiovascular hospitalizations in Catalonia. The effect of cold spells was greater when including the 7 subsequent days. Such knowledge might be useful to develop strategies to reduce the impact of extreme temperature episodes on human health.

No increased risk of Guillain-Barré syndrome after human papilloma virus vaccine: A self-controlled case-series study in England

ObjectiveTo investigate the risk of Guillain-Barré syndrome (GBS) after human papilloma virus (HPV) vaccine given to 12–18year old girls in England. MethodsHospital Episode Statistics (HES) were searched using data to March 2016 to identify incident cases of GBS in female patients aged from 11 to 20years eligible to have received the HPV vaccine since its introduction as a 3 dose schedule in September 2008. Diagnosis was confirmed by the case’s general practitioner (GP) who also provided HPV vaccination dates. The risk of admission within 3months (primary risk window) 6 and 12months of any dose was assessed using the self-controlled case-series (SCCS) method in vaccinated girls with age, season and time-period adjustment. The risk before and after the change in 2012 from bivalent vaccine to quadrivalent vaccine was also assessed. ResultsA total 244 episodes were initially identified which reduced to 101 episodes in 100 girls when just including cases where the GP could be contacted, at least one vaccine dose was given, and GBS was confirmed or classed as probable. Nine, 14 and 24GBS admissions occurred within 3, 6, 12months of a dose respectively. The relative incidence (RI) for the 3month risk period was 1.04 (95% confidence interval 0.47–2.28), for the 6month period 0.83 (0.41–1.69) and for the 12month period 1.10 (0.57–2.14). When restricting to 79 confirmed cases the RI in the 3month risk period was 1.26 (0.55–2.92) and the RI 1.61 (0.39–6.54) for quadrivalent vaccine compared to 0.84 (0.30–2.34) for bivalent. ConclusionWe found no evidence of an increased risk of GBS following HPV vaccination in England and, based on the upper end of the 95% CI for the RI and the number of HPV vaccine doses given in England, can exclude a risk of about 1 per million doses.

Antibiotic use as a marker of acute infection and risk of first and recurrent venous thrombosis.

A role for transient infections in the aetiology of venous thrombosis (VT) has been suggested. This study aimed to determine whether individuals who receive antibiotic treatment (as a proxy for infections) have an increased risk of first and recurrent VT and whether infections should be seen as a provoking risk factor for VT. We used the self-controlled case series method to study the risk of first VT during antibiotic prescriptions. The risk of recurrent VT during antibiotic use was estimated by of time-dependent Cox-regression. A total of 2547 patients with a first VT were included and followed for a median of 5·9years for recurrence (1999-2010), in whom 114 first events occurred during antibiotic use. We found a five-fold increased risk of first VT during antibiotic treatment: [incidence-rate-ratio 5·0; 95% confidence interval (CI), 4·0-6·1]. Antibiotic use was associated with a 2·0-fold (95% CI, 1·1-4·0) increased risk of recurrent VT. Patients with an unprovoked first VT who used antibiotics shortly before this event, had a similar risk of recurrence as patients with a provoked first VT (adjusted hazard ratio 1·1; 95% CI, 0·7-1·7). Individuals who receive antibiotics have an increased risk of first and recurrent VT and infections should be considered a provoking risk factor for VT.

Bias and estimation under misspecification of the risk period in self‐controlled case series studies

The self-controlled case series (SCCS) method is useful for estimating the relative incidence (RI) of acute events, such as adverse events (AEs) during a specified risk period following an exposure (e.g., 6-week period after vaccinations or 30-day period after infection-related hospitalizations). In practice, the "optimal" risk period is unknown and must be specified. To date, two approaches are available to guide the specification of the risk period. Both methods do not fully utilize the nature of the bias due to misspecification, which to date has not been characterized. Thus, we elucidate the bias of SCCS estimate of the RI when the risk period is misspecified. We then propose a novel method that more effectively estimates the optimal risk period and the associated RI of AEs. The new method incorporates information on the functional form of the bias. Efficacy of the proposed approach is illustrated with substantial reduction in bias and variance in simulation studies. The proposed method is illustrated with two SCCS studies to determine the (1) risk of idiopathic thrombocytopenic purpura after measles-mumps-rubella vaccination in children and (2) risk of cardiovascular events after infection-related hospitalizations in older patients on dialysis.

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).

Self controlled case series methods: an alternative to standard epidemiological study designs.

The self controlled case series (SCCS) method is an epidemiological study design for which individuals act as their own control—ie, comparisons are made within individuals. Hence, only individuals who have experienced an event are included and all time invariant confounding is eliminated. The temporal association between a transient exposure and an event is estimated. SCCS was originally developed for evaluation of vaccine safety, but has since been applied in a range of settings where exact information on the size of the population at risk is lacking or identification of an appropriate comparison group is difficult—eg, for studies of adverse effects of drug treatments. We provide an overview of the SCCS method, with examples of its use, discuss limitations, assumptions, and potential biases that can arise where assumptions are not met, and provide solutions and examples of good practice.

The risk of intussusception following monovalent rotavirus vaccination in England: A self-controlled case-series evaluation

ObjectiveTo investigate the risk of intussusception after monovalent rotavirus vaccine (RV1) given to infants aged 2 and 3 months in England. MethodsHospital Episode Statistics (HES) were used to identify infants aged 48–183 days admitted between 11/03/2013 and 31/10/2014 with intussusception. Diagnosis was confirmed from medical records and HES procedure codes. Vaccination status was obtained from general practitioners. The risk of admission within 1–7 and 8–21 days of vaccination was analysed using the self-controlled case-series (SCCS) method with age effect adjustment by including historical data before RVI introduction in July 2013. ResultsA total of 119 cases were identified during the study period and intussusception confirmed in 95 of whom 39 were vaccinated 1–21 days before onset. An increased relative incidence (RI) in this period was found, 4.53 (95% confidence interval 2.34–8.58) and 2.60 (1.43–4.81) respectively after the 1st and 2nd doses with an attributable risk of 1.91 and 1.49 per 100,000 doses respectively. The peak risk was 1–7 days after the first dose, RI 13.81 (6.44–28.32), with an estimated 93% of the 15 cases being vaccine-attributable. Mean interval between onset and admission, and clinical features were similar between vaccine-associated and background cases. Despite intussusception being a contraindication to rotavirus vaccination, 10 infants received a further dose; none had a recurrence. The RIs in a meta-analysis combing our results with Australia, Mexico, Brazil and Singapore using RV1, a 2, 4 month schedule and SCCS gave pooled RI estimates of 2.35 (1.45–3.8) and 1.77 (1.29–2.43) in the 21 day period after the 1st and 2nd doses, respectively. The earlier age at the 2nd dose in England did not affect the risk. ConclusionWe estimate that the RVI programme causes around 21 intussusception admissions annually in England but, since it prevents around 25,000 gastro-intestinal infection admissions, its benefit/risk profile remains strongly positive.

Risk of solid organ transplant rejection following vaccination with seasonal trivalent inactivated influenza vaccines in England: A self-controlled case-series

BackgroundAnnual seasonal influenza vaccination is recommended for transplant recipients. No formal pharmacoepidemiology study has been published on the association between solid organ transplant (SOT) rejection and vaccination with seasonal trivalent inactivated influenza vaccines (TIIVs). MethodsThe risk of SOT (liver, kidney, lung, heart or pancreas) rejection after TIIV vaccination was assessed using a self-controlled case-series method (NCT01715792). SOT recipients in England with transplant rejection were selected from the Clinical Practice Research Datalink and linked Hospital Episode Statistics inpatient data. The study period (September 2006 to August 2009) encompassed three consecutive influenza seasons. We calculated the relative incidence (RI) of SOT rejection between the 30- and 60-day post-vaccination risk periods and the control periods (any follow-up period excluding risk periods), using a Poisson regression model. ResultsIn seasons 2006/07, 2007/08, 2008/09 and pooled seasons, 132, 136, 168 and 375 subjects, respectively, experienced at least one transplant rejection; approximately half (45%–51%) of these subjects had received a TIIV. For season 2006/07, the RI of rejection of any organ, adjusted for time since transplantation, was 0.74 (95% CI: 0.24–2.28) and 0.58 (95% CI: 0.24–1.38) during the 30-day and 60-day risk periods, respectively. Corresponding RIs for season 2007/08 were 1.21 (95% CI: 0.55–2.64) and 1.31 (95% CI: 0.69–2.48); for season 2008/09, 0.99 (95% CI: 0.43–2.28) and 0.64 (95% CI: 0.31–1.33); and for pooled seasons 1.01 (95% CI: 0.58–1.76) and 0.88 (95% CI: 0.56–1.38). The results of a separate analysis of kidney rejections and analyses that took into account additional potential confounders were consistent with those of the main analyses, with 95% CIs including 1 and upper limits below 3. ConclusionThis study provides reassuring evidence of the safety profile of TIIVs in SOT recipients, thus supporting current recommendations to vaccinate this risk group annually.

Evaluation of the Intussusception Risk after Pentavalent Rotavirus Vaccination in Finnish Infants.

BackgroundAn association between rotavirus immunisation and intussusception (IS) has been suggested with present rotavirus vaccines in post-licensure studies. In Finland, rotavirus vaccination programme was implemented in September 2009 using a 2, 3, and 5 months schedule with the pentavalent rotavirus vaccine. By the end of 2013, it is estimated that 719 000 rotavirus vaccine doses have been given in the national programme of which 240 000 were first doses. Nationwide register allows us to evaluate the association between rotavirus vaccination and IS.Methods and MaterialsCases of IS diagnosed during 1999–2013 were identified from National Hospital Discharge Register. All cases under 250 days of age diagnosed during 2009–2013 were confirmed by reviewing medical charts. Self-controlled case-series method was used to assess the risk of IS during 1–21 days compared to 22–42 days post vaccination.FindingsIn register data the relative incidence of IS at 2 months of age between the post and pre vaccination era was 9.1 (95%CI 2.0–84.3). We identified 22 verified cases with date of admission less than 43 days after any of the three rotavirus vaccine doses. The incidence of IS in the risk period after the 1st dose relative to the control period was 2.0 (95% CI 0.5–8.4; p = 0.34.) Number of excess IS cases per 100 000 first vaccine doses was therefore estimated to be 1.04 (95% CI 0.0–2.5), i.e. one additional IS case per 96 000 first doses of rotavirus vaccine (95% CI 54 600 to ∞). There was no risk detected after 2nd and 3rd doses.ConclusionThe finding is in line with the recent published estimates. The benefits of rotavirus immunisation programme outweigh possible small risks of intussusception.

Evaluating efficiency and statistical power of self-controlled case series and self-controlled risk interval designs in vaccine safety

ABSTRACTThe self-controlled case series (SCCS) and self-controlled risk interval (SCRI) designs have recently become widely used in the field of post-licensure vaccine safety monitoring to detect potential elevated risks of adverse events following vaccinations. The SCRI design can be viewed as a subset of the SCCS method in that a reduced comparison time window is used for the analysis. Compared to the SCCS method, the SCRI design has less statistical power due to fewer events occurring in the shorter control interval. In this study, we derived the asymptotic relative efficiency (ARE) between these two methods to quantify this loss in power in the SCRI design. The equation is formulated as (a: control window-length ratio between SCRI and SCCS designs; b: ratio of risk window length and control window length in the SCCS design; and : relative risk of exposed window to control window). According to this equation, the relative efficiency declines as the ratio of control-period length between SCRI and SCCS methods decreases, or with an increase in the relative risk . We provide an example utilizing data from the Vaccine Safety Datalink (VSD) to study the potential elevated risk of febrile seizure following seasonal influenza vaccine in the 2010–2011 season.

The factorized self-controlled case series method

We provide a hierarchical Bayesian model for estimating the effects of transient drug exposures on a collection of health outcomes, where the effects of all drugs on all outcomes are estimated simu...

Acute Cardiovascular Events after Herpes Zoster: A Self-Controlled Case Series Analysis in Vaccinated and Unvaccinated Older Residents of the United States.

BackgroundHerpes zoster is common and can have serious consequences. Additionally, emerging data suggest an increased risk of acute cardiovascular events following herpes zoster. However, to our knowledge, existing association studies compare outcomes between individuals and are therefore vulnerable to between-person confounding. In this study, we used a within-person study design to quantify any short-term increased risk of acute cardiovascular events (stroke and myocardial infarction [MI]) after zoster and to assess whether zoster vaccination modifies this association.Methods and FindingsThe self-controlled case series method was used to estimate rates of stroke and acute MI in defined periods after herpes zoster compared to other time periods, within individuals. Participants were fully eligible Medicare beneficiaries aged ≥65 y with a herpes zoster diagnosis and either an ischemic stroke (n = 42,954) or MI (n = 24,237) between 1 January 2006 and 31 December 2011. Age-adjusted incidence ratios (IRs) for stroke and MI during predefined periods up to 12 mo after zoster relative to unexposed time periods were calculated using conditional Poisson regression. We observed a marked increase in the rate of acute cardiovascular events in the first week after zoster diagnosis: a 2.4-fold increased ischemic stroke rate (IR 2.37, 95% CI 2.17–2.59) and a 1.7-fold increased MI rate (IR 1.68, 95% CI 1.47–1.92), followed by a gradual resolution over 6 mo. Zoster vaccination did not appear to modify the association with MI (interaction p-value = 0.44). We also found no evidence for a difference in the IR for ischemic stroke between vaccinated (IR 1.14, 95% CI 0.75–1.74) and unvaccinated (IR 1.78, 95% CI 1.68–1.88) individuals during the first 4 wk after zoster diagnosis (interaction p-value = 0.28). The relatively few vaccinated individuals limited the study’s power to assess the role of vaccination.ConclusionsStroke and MI rates are transiently increased after exposure to herpes zoster. We found no evidence for a role of zoster vaccination in these associations. These findings enhance our understanding of the temporality and magnitude of the association between zoster and acute cardiovascular events.

Comparative Effectiveness of Generic Imatinib and Brand-Name Imatinib for the Treatment of Chronic Myeloid Leukemia

Background: Generic versions of imatinib (GEN) have been approved for use in Canada for chronic myeloid leukemia, chronic phase (CML-CP) on the basis of bioequivalence studies and were reimbursed in Québec starting from October 2013. Molecular responses with GEN have not yet been examined in detail. This study assesses the risk of diminished molecular response in switchers from brand-name imatinib (BN) to GEN and compares the effectiveness of initiating first-line GEN and first-line BN.Methods: Prospective individual patient data were available from nine hospitals participating in the Québec CML registry. To allow equipoise between GEN and BN, we focused on stable BN users at the time of GEN market entry, of which some were subsequently switched to GEN. We further selected only those who had a 1-log rise in international reporting scale (IS) BCR-ABL1 transcript level and conducted a self-controlled case series study (SCSS).1 Using SCSS, each patient contributed follow-up for BN use, and for GEN use (if a switch occurred). The analysis used pooled BN and GEN person-time and compared the odds ratio (OR) of 1-log rise during GEN and BN treatment using conditional Poisson regression. A second analysis used a cohort of initiators of BN and GEN from 2013 and onwards. Kaplan Meier (KM) analyses were used to estimate the cumulative incidence of early molecular response (EMR) corresponding to < 10% IS. Cox proportional hazards models were used to estimate age-adjusted hazard ratio (HR) with 95% confidence intervals (CI) for EMR with GEN use, when compared with BN use.Results: We identified 184 patients treated with BN, 38 who were switched from BN to GEN, and 5 who used GEN only. For the SCSS analysis we included 23 patients, of which 17 had 1-log rise during BN use and 6 during GEN use. All patients had achieved major molecular response (MMR) prior to cohort entry (Table). Mean follow-up was 1.45±0.43 years. Overall, the use of GEN was associated with an increased incidence of 1- log rise (OR: 3.34, 95% CI: 0.33-33.68), although not reaching statistical significance. Ten of 23 rises in BCR-ABL1 levels were subsequently confirmed (7 in BN and 3 in GEN). Eleven patients lost MMR (IS>0.1%), 9 during BN use and 2 during GEN use. The cohort of first-line imatinib included 11 patients, 4 GEN and 7 BN. GEN users were slightly older (61 vs 53, GEN vs BN), and Sokal scores were comparable (low, 2 vs 4; intermediate, 2 vs 3). There was no clear separation of the EMR curves (Figure). However, the adjusted HR of EMR with GEN was 0.38 (95% CI: 0.07-2.15), compared with BN.Conclusions: While these analyses are preliminary, our results call for an initiative on a larger scale to examine the clinical effectiveness of generic imatinib for CML-CP.1. Whitaker HJ, Farrington CP, Spiessens B, Musonda P. Tutorial in biostatistics: the self-controlled case series method. Stat Med. 2006;25(10):1768-1797.Table 1Baseline characteristics of the self-controlled case series cohort (n=23)CharacteristicValueMean age, years (SD)62.87 (15.4)Female sex (n, %)9 (39.1)Mean number of concomitant medications (SD)1.07 (2.2)Mean years of brand-name imatinib use (SD)6.85 (2.8)Number major molecular response (%)23 (100.0) [Display omitted] DisclosuresChamakhi:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Delage:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Laneuville:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Mollica:Pfizer: Consultancy; Novartis: Consultancy; BMS: Consultancy. Olney:Cellgene: Honoraria; Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Busque:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Assouline:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy.

Febrile seizures after 2009 influenza A (H1N1) vaccination and infection: a nationwide registry-based study.

BackgroundDuring the 2009 influenza A (H1N1) pandemic, a monovalent pandemic strain vaccine containing the oil-in-water adjuvant AS03 (Pandemrix®) was offered to the Norwegian population. The coverage among children reached 54 %. Our aim was to estimate the risk of febrile seizure in children after exposure to pandemic influenza vaccination or infection.MethodsThe study population comprised 226,889 children born 2006–2009 resident in Norway per October 1st, 2009. Febrile seizure episodes were defined by emergency hospital admissions / emergency outpatient hospital care with International Classification of Diseases, Version 10, codes R56.0 or R56.8. The self-controlled case series method was applied to estimate incidence rate ratios (IRRs) in pre-defined risk periods compared to the background period. The total observation window was ± 180 days from exposure day. Among 113,068 vaccinated children, 656 (0.6 %) had at least one febrile seizure episode.ResultsThe IRR of febrile seizures 1–3 days after vaccination was 2.00 (95 % confidence interval [CI]: 1.15–3.51). In the period 4–7 days after vaccination, no increased risk was observed. Among the 8172 children diagnosed with pandemic influenza, 84 (1.0 %) had at least one febrile seizure episode. The IRR of febrile seizures on the same day as a diagnosis of influenza was 116.70 (95 % CI: 62.81–216.90). In the period 1–3 days after a diagnosis of influenza, a tenfold increased risk was observed (IRR 10.12, 95 % CI: 3.82 – 26.82).ConclusionsIn this large population-based study with precise timing of exposures and outcomes, we found a twofold increased risk of febrile seizures 1–3 days after pandemic influenza vaccination. However, we found that pandemic influenza infection was associated with a much stronger increase in risk of febrile seizures.

Active Surveillance for Adverse Events After a Mass Vaccination Campaign With a Group A Meningococcal Conjugate Vaccine (PsA-TT) in Mali.

Background. The monovalent meningococcal A conjugate vaccine (PsA-TT, MenAfriVac) was developed for use in the “meningitis belt” of sub-Saharan Africa. Mali was 1 of 3 countries selected for early introduction. As this is a new vaccine, postlicensure surveillance is particularly important to identify and characterize possible safety issues.Methods. The national vaccination campaign was phased from September 2010 to November 2011. We conducted postlicensure safety surveillance for PsA-TT in 40 government clinics from southern Mali serving approximately 400 000 people 1–29 years of age. We conducted analyses with individual-level data and population-level data, and we calculated rates of adverse events using the conditional exact test, a modified vaccine cohort risk interval method, and a modified self-controlled case series method for each outcome of interest, including 18 prespecified adverse events and 18 syndromic categories.Results. An increased rate of clinic visits for fever within 3 days after vaccination was found using multiple methods for all age groups. Although other signals were found with some methods, complete assessment of all other prespecified outcomes and syndromic categories did not reveal that PsA-TT was consistently associated with any other health problem.Conclusions. No new safety concerns were identified in this study. These results are consistent with prelicensure data and other studies indicating that PsA-TT is safe. The approach presented could serve as a model for future active postlicensure vaccine safety monitoring associated with large-scale immunization campaigns in low-income countries.

Flexible modelling of vaccine effect in self-controlled case series models.

The self-controlled case series (SCCS) method, commonly used to investigate the safety of vaccines, requires information on cases only and automatically controls all age-independent multiplicative confounders, while allowing for an age-dependent baseline incidence. Currently, the SCCS method represents the time-varying exposures using step functions with pre-determined cut points. A less prescriptive approach may be beneficial when the shape of the relative risk function associated with exposure is not known a priori, especially when exposure effects can be long-lasting. We therefore propose to model exposure effects using flexible smooth functions. Specifically, we used a linear combination of cubic M-splines which, in addition to giving plausible shapes, avoids the integral in the log-likelihood function of the SCCS model. The methods, though developed specifically for vaccines, are applicable more widely. Simulations showed that the new approach generally performs better than the step function method. We applied the new method to two data sets, on febrile convulsion and exposure to MMR vaccine, and on fractures and thiazolidinedione use.