Research Article: Incidence rates of narcolepsy diagnoses in Taiwan, Canada, and Europe: The use of statistical simulation to evaluate methods for the rapid assessment of potential safety issues on a population level in the SOMNIA study

Date Published: October 17, 2018

Publisher: Public Library of Science

Author(s): Caitlin N. Dodd, Maria de Ridder, Wan-Ting Huang, Daniel Weibel, Maria Giner-Soriano, Silvia Perez-Vilar, Javier Diez-Domingo, Lawrence W. Svenson, Salahddin M. Mahmud, Bruce Carleton, Monika Naus, Jeffrey C. Kwong, Brian J. Murray, Lisen Arnheim-Dahlstrom, Lars Pedersen, Rosa Morros, Francisco Javier Puertas, Steven Black, Miriam Sturkenboom, Raffaele Ferri.


Vaccine safety signals require investigation, which may be done rapidly at the population level using ecological studies, before embarking on hypothesis-testing studies. Incidence rates were used to assess a signal of narcolepsy following AS03-adjuvanted monovalent pandemic H1N1 (pH1N1) influenza vaccination among children and adolescents in Sweden and Finland in 2010. We explored the utility of ecological data to assess incidence of narcolepsy following exposure to pandemic H1N1 virus or vaccination in 10 sites that used different vaccines, adjuvants, and had varying vaccine coverage.

We calculated incidence rates of diagnosed narcolepsy for periods defined by influenza virus circulation and vaccination campaign dates, and used Poisson regression to estimate incidence rate ratios (IRRs) comparing the periods during which wild-type virus circulated and after the start of vaccination campaigns vs. the period prior to pH1N1 virus circulation. We used electronic health care data from Sweden, Denmark, the United Kingdom, Canada (3 provinces), Taiwan, Netherlands, and Spain (2 regions) from 2003 to 2013. We investigated interactions between age group and adjuvant in European sites and conducted a simulation study to investigate how vaccine coverage, age, and the interval from onset to diagnosis may impact the ability to detect safety signals.

Incidence rates of narcolepsy varied by age, continent, and period. Only in Taiwan and Sweden were significant time-period-by-age-group interactions observed. Associations were found for children in Taiwan (following pH1N1 virus circulation) and Sweden (following vaccination). Simulations showed that the individual-level relative risk of narcolepsy was underestimated using ecological methods comparing post- vs. pre-vaccination periods; this effect was attenuated with higher vaccine coverage and a shorter interval from disease onset to diagnosis.

Ecological methods can be useful for vaccine safety assessment but the results are influenced by diagnostic delay and vaccine coverage. Because ecological methods assess risk at the population level, these methods should be treated as signal-generating methods and drawing conclusions regarding individual-level risk should be avoided.

Partial Text

In August 2010, a safety signal of narcolepsy following AS03-adjuvanted pdm(09)H1N1 influenza vaccine Pandemrix® was reported in Finland and Sweden among children and adolescents [1]. Other rapid risk assessment studies conducted in the European Union (EU) did not show changes in incidence rates of narcolepsy diagnoses, except in Finland, Sweden, and Norway [2], all countries that achieved high coverage rates with Pandemrix. Subsequent hypothesis-testing studies showed associations; these had high within- and between-study variation [3]. In China, where vaccine coverage was very low, a 3-fold increase in narcolepsy onset was reported following the peak of the pandemic [4].

Narcolepsy diagnosis incidence rates were evaluated in ten sites representing seven countries spanning three continents (Taiwan (TW), Canada (CA) [Manitoba, Alberta, and British Columbia], The Netherlands (NL), The United Kingdom (UK), Sweden (SE), Denmark (DK), and Spain (ES) [Valencia and Cataluña]) using population-based electronic healthcare databases originating from general practitioners (GPs) (UK, ES, NL) or claims/record linkage databases (SE, DK, TW [16–18], and CA) (S1 Table).

Evaluation of incidence rates on a population level can be done relatively quickly in countries/regions with accessible population-based electronic health care databases. This is useful for assessing potential vaccine safety signals. In order to calculate rates quickly in a standardized manner, harmonization of data into simple input files in a common format allowed for the pooling and sharing of data across three continents. The method was capable of identifying the signal in Sweden in 5- to 19-year olds.

Ecological methods can be useful in assessment of vaccine safety but it is important for investigators to understand the impacts of masking by strata not at risk, patterns of onset and diagnosis, and vaccine coverage. What appears to be an estimate of no effect could be valid or, as shown in our simulations, could be an underestimation.




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