Mees Mosseveld

The incidence of narcolepsy in Europe: Before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns

BACKGROUNDnIn August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification.nnnMETHODSnWe used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000-2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom.nnnRESULTSnOverall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95% CI: 0. 90-0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women>men) and around 60 years of age. In the age group 5-19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95% CI: 1.1-3.1) in Denmark, 6.4 (95% CI: 4.2-9.7) in Finland and 7.5 (95% CI: 5.2-10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time.nnnCONCLUSIONSnThe results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail.

Electronic Alerts Versus On-Demand Decision Support to Improve Dyslipidemia Treatment: A Cluster Randomized Controlled Trial

Background— Indirect evidence shows that alerting users with clinical decision support systems seems to change behavior more than requiring users to actively initiate the system. However, randomized trials comparing these methods in a clinical setting are lacking. We studied the effect of both alerting and on-demand decision support with respect to screening and treatment of dyslipidemia based on the guidelines of the Dutch College of General Practitioners. Methods and Results— In a clustered randomized trial design, 38 Dutch general practices (77 physicians) and 87 886 of their patients (39 433 men 18 to 70 years of age and 48 453 women 18 to 75 years of age) who used the ELIAS electronic health record participated. Each practice was assigned to receive alerts, on-demand support, or no intervention. We measured the percentage of patients screened and treated after 12 months of follow-up. In the alerting group, 65% of the patients requiring screening were screened (relative risk versus control=1.76; 95% confidence interval, 1.41 to 2.20) compared with 35% of patients in the on-demand group (relative risk versus control=1.28; 95% confidence interval, 0.98 to 1.68) and 25% of patients in the control group. In the alerting group, 66% of patients requiring treatment were treated (relative risk versus control=1.40; 95% confidence interval, 1.15 to 1.70) compared with 40% of patients (relative risk versus control=1.19; 95% confidence interval, 0.94 to 1.50) in the on-demand group and 36% of patients in the control group. Conclusion— The alerting version of the clinical decision support systems significantly improved screening and treatment performance for dyslipidemia by general practitioners.

Guillain-Barré Syndrome and Adjuvanted Pandemic Influenza A (H1N1) 2009 Vaccines: A Multinational Self-Controlled Case Series in Europe

Background The risk of Guillain-Barré syndrome (GBS) following the United States 1976 swine flu vaccination campaign in the USA led to enhanced active surveillance during the pandemic influenza (A(H1N1)pdm09) immunization campaign. This study aimed to estimate the risk of GBS following influenza A(H1N1)pdm09 vaccination. Methods A self-controlled case series (SCCS) analysis was performed in Denmark, Finland, France, Netherlands, Norway, Sweden, and the United Kingdom. Information was collected according to a common protocol and standardised procedures. Cases classified at levels 1–4a of the Brighton Collaboration case definition were included. The risk window was 42 days starting the day after vaccination. Conditional Poisson regression and pooled random effects models estimated adjusted relative incidences (RI). Pseudo likelihood and vaccinated-only methods addressed the potential contraindication for vaccination following GBS. Results Three hundred and three (303) GBS and Miller Fisher syndrome cases were included. Ninety-nine (99) were exposed to A(H1N1)pdm09 vaccination, which was most frequently adjuvanted (Pandemrix and Focetria). The unadjusted pooled RI for A(H1N1)pdm09 vaccination and GBS was 3.5 (95% Confidence Interval (CI): 2.2–5.5), based on all countries. This lowered to 2.0 (95% CI: 1.2–3.1) after adjustment for calendartime and to 1.9 (95% CI: 1.1–3.2) when we accounted for contra-indications. In a subset (Netherlands, Norway, and United Kingdom) we further adjusted for other confounders and there the RI decreased from 1.7 (adjusted for calendar month) to 1.4 (95% CI: 0.7–2.8), which is the main finding. Conclusion This study illustrates the potential of conducting European collaborative vaccine safety studies. The main, fully adjusted analysis, showed that the RI of GBS was not significantly elevated after influenza A(H1N1)pdm09 vaccination (RIu200a=u200a1.4 (95% CI: 0.7–2.8). Based on the upper limits of the pooled estimate we can rule out with 95% certainty that the number of excess GBS cases after influenza A(H1N1)pdm09 vaccination would be more than 3 per million vaccinated.

Validation study in four health-care databases: upper gastrointestinal bleeding misclassification affects precision but not magnitude of drug-related upper gastrointestinal bleeding risk

OBJECTIVEnTo evaluate the accuracy of disease codes and free text in identifying upper gastrointestinal bleeding (UGIB) from electronic health-care records (EHRs).nnnSTUDY DESIGN AND SETTINGnWe conducted a validation study in four European electronic health-care record (EHR) databases such as Integrated Primary Care Information (IPCI), Health Search/CSD Patient Database (HSD), ARS, and Aarhus, in which we identified UGIB cases using free text or disease codes: (1) International Classification of Disease (ICD)-9 (HSD, ARS); (2) ICD-10 (Aarhus); and (3) International Classification of Primary Care (ICPC) (IPCI). From each database, we randomly selected and manually reviewed 200 cases to calculate positive predictive values (PPVs). We employed different case definitions to assess the effect of outcome misclassification on estimation of risk of drug-related UGIB.nnnRESULTSnPPV was 22% [95% confidence interval (CI): 16, 28] and 21% (95% CI: 16, 28) in IPCI for free text and ICPC codes, respectively. PPV was 91% (95% CI: 86, 95) for ICD-9 codes and 47% (95% CI: 35, 59) for free text in HSD. PPV for ICD-9 codes in ARS was 72% (95% CI: 65, 78) and 77% (95% CI: 69, 83) for ICD-10 codes (Aarhus). More specific definitions did not have significant impact on risk estimation of drug-related UGIB, except for wider CIs.nnnCONCLUSIONSnICD-9-CM and ICD-10 disease codes have good PPV in identifying UGIB from EHR; less granular terminology (ICPC) may require additional strategies. Use of more specific UGIB definitions affects precision, but not magnitude, of risk estimates.

A Technical Infrastructure to Conduct Randomized Database Studies Facilitated by a General Practice Research Database

General practice research databases are increasingly used to study intended and unintended effects of treatments. However, confounding by indication remains a major problem. The randomized database study methodology has been proposed as a method to combine the strengths of observational database (generalizability) and the strength of the randomized clinical trial (RCT) design (randomization). We developed an infrastructure that enables the execution of randomized database studies with treatment randomization facilitated by a general practice research database. The requirements posed by the methodology of randomized database studies were facilitated by software components. Our assessment showed that it is technically possible to conduct randomized trials in general practice according to the randomized database design. The infrastructure facilitated the conduct of randomized database studies in general practice but some practical difficulties and methodological issues remain. The technical infrastructure seems to be both promising and potentially feasible to facilitate future randomized database studies, although the methodology needs to be evaluated in more detail.

Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease.

BackgroundNon-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. It affects an estimated 20% of the general population, based on cohort studies of varying size and heterogeneous selection. However, the prevalence and incidence of recorded NAFLD diagnoses in unselected real-world health-care records is unknown. We harmonised health records from four major European territories and assessed age- and sex-specific point prevalence and incidence of NAFLD over the past decade.MethodsData were extracted from The Health Improvement Network (UK), Health Search Database (Italy), Information System for Research in Primary Care (Spain) and Integrated Primary Care Information (Netherlands). Each database uses a different coding system. Prevalence and incidence estimates were pooled across databases by random-effects meta-analysis after a log-transformation.ResultsData were available for 17,669,973 adults, of which 176,114 had a recorded diagnosis of NAFLD. Pooled prevalence trebled from 0.60% in 2007 (95% confidence interval: 0.41–0.79) to 1.85% (0.91–2.79) in 2014. Incidence doubled from 1.32 (0.83–1.82) to 2.35 (1.29–3.40) per 1000 person-years. The FIB-4 non-invasive estimate of liver fibrosis could be calculated in 40.6% of patients, of whom 29.6–35.7% had indeterminate or high-risk scores.ConclusionsIn the largest primary-care record study of its kind to date, rates of recorded NAFLD are much lower than expected suggesting under-diagnosis and under-recording. Despite this, we have identified rising incidence and prevalence of the diagnosis. Improved recognition of NAFLD may identify people who will benefit from risk factor modification or emerging therapies to prevent progression to cardiometabolic and hepatic complications.

Het effect van elektronische herinneringen bij de behandeling van dislipidemie

samenvattingVan Wyk JT, Van Wijk MAM, Sturkenboom MCJM, Mosseveld M, Moorman PW, Van der Lei J. Het effect van elektronische herinneringen bij de behandeling van dislipidemie. Huisarts Wet 2009;52(10):490-6.n Doel Sommige systemen ter ondersteuning van klinische besluitvorming (Clinical Decision Support Systems, CDSS) genereren automatisch herinneringen voor de gebruiker. Andere systemen moeten actief door de gebruiker worden opgestart. Er zijn geen gerandomiseerde onderzoeken die deze twee werkwijzen in een klinische omgeving vergelijken. We onderzochten het effect van de geautomatiseerde herinneringen en dat van niet-geautomatiseerde ondersteuning (‘op verzoek’). Dat deden we in het kader van de besluitvorming rond de screening en behandeling van dislipidemie, gebaseerd op de richtlijnen van het NHG.Methode We deden een geclusterd gerandomiseerd onderzoek, waaraan 36 Nederlandse huisartsenpraktijken (77 artsen) met 87.886 patiënten (39.433 mannen in de leeftijd van 18 tot 70 jaar, 48.453 vrouwen in de leeftijd van 18 tot 75 jaar) deelnamen. We wezen de praktijken toe aan de herinneringgroep, de op-verzoekgroep of de controlegroep (geen interventie). We berekenden het percentage patiënten dat gescreend en behandeld werd na 12 maanden follow-up.Resultaten In de herinneringgroep werd 65% van de patiënten die gescreend moesten worden, daadwerkelijk gescreend, in de controlegroep lag dat percentage op 25% (RR tegen controle = 1,76; 95%-BI 0,98-1,68). In de herinneringgroep werd 66% van de patiënten die behandeling nodig hadden daadwerkelijk behandeld (RR tegen controle = 1,40; 95%-BI 1,15-1,70) vergeleken met 39% van de patiënten (RR tegen controle = 1,19; 95%-BI 0,94-1,50) in de op-verzoekgroep en 36% van de patiënten in de controlegroep.Conclusie De versie van de CDSS met de herinnering gaf een significante verbetering van de mate van screening en behandeling van dislipidemie door huisartsen.

Impact of different assumptions on estimates of childhood diseases obtained from health care data: A retrospective cohort study

Accurate estimates of disease incidence in children are required to support pediatric drug development. Analysis of electronic health care records (EHR) may yield such estimates but pediatric‐specific methods are lacking. We aimed to understand the impact of assumptions regarding duration of disease episode and length of run‐in period on incidence estimates from EHRs.