Temporal association between the A/H1N1 2009 influenza virus pandemic and vaccination programme in Norway.

<p>(A) Number of laboratory-confirmed cases of A/H1N1 2009 pandemic influenza virus reported through the surveillance system and number of A/H1N1 2009 pandemic influenza virus vaccinees divided by 100, by week of 2009–2010. (B) Cumulative number of laboratory-confirmed cases of A/H1N1 2009 pandemic influenza virus reported through the surveillance system and cumulative number of A/H1N1 2009 pandemic influenza virus vaccinees divided by 100. The first four weeks of 2010 are designated as weeks 54–57.</p

Number of symptomatic A/H1N1 2009 pandemic influenza cases projected by the model compared with the observed number of laboratory-confirmed A/H1N1 2009 pandemic influenza cases.

<p>(A) all ages; (B) age 0–<10 years; (C) age 10–<20 years; (D) age 20–<30 years; (E) age 30–<50 years (pooled); (F) age 50+ years. Black: Model-projected cases scaled down to account for age-specific under-reporting factors. Red: Observed laboratory-confirmed cases reported to the surveillance system. Week number refers to 2009, and the first four weeks of 2010 are designated as weeks 54–57.</p

Model parameters estimated by calibration.

<p>Model parameters estimated by calibration.</p

Incidence of symptomatic A/H1N1 2009 pandemic influenza virus infection and percentage of vaccinated individuals already infected before vaccination in Norway during the 2009 pandemic.

<p>Middle column: Model-projected percentage with symptomatic A/H1N1 2009 pandemic influenza virus infection, by age and pooled across all age groups. Right column: Model-projected percentage of vaccinees at the end of the pandemic who were infected with A/H1N1 2009 pandemic influenza virus before receiving vaccination in Norway, by age and pooled across all age groups. Base case.</p

Percentage of individuals in Norway vaccinated with adjuvanted (AS03) A/H1N1 2009 pandemic influenza vaccine during the A/H1N1 2009 influenza virus pandemic.

<p>Percentage of individuals in Norway vaccinated with adjuvanted (AS03) A/H1N1 2009 pandemic influenza vaccine during the A/H1N1 2009 influenza virus pandemic.</p

Estimated age-specific under-reporting factors.

<p>Estimated age-specific under-reporting factors.</p

Additional file 1: Table S1. of Estimates of hospitalization attributable to influenza and RSV in the US during 1997–2009, by age and risk status

Seasonal burden of hospitalization attributable to influenza and RSV by season in the US, 1997–2009 (respiratory broad outcome, any mention). 1Annual mean rate per 100,000 population; *Data included up to 31st March 2009; CI: confidential interval. Table S2. Number of hospitalizations attributable to influenza and RSV according to risk status and age in the US, 1997–2009 (respiratory broad outcome, any mention). SD: standard deviation; RSV: respiratory syncytial virus. (DOCX 42 kb

Application of Probabilistic Multiple-Bias Analyses to a Cohort- and a Case-Control Study on the Association between <i>Pandemrix</i>^™and Narcolepsy

<div><p>Background</p><p>An increase in narcolepsy cases was observed in Finland and Sweden towards the end of the 2009 H1N1 influenza pandemic. Preliminary observational studies suggested a temporal link with the pandemic influenza vaccine <i>Pandemrix</i>™, leading to a number of additional studies across Europe. Given the public health urgency, these studies used readily available retrospective data from various sources. The potential for bias in such settings was generally acknowledged. Although generally advocated by key opinion leaders and international health authorities, no systematic quantitative assessment of the potential joint impact of biases was undertaken in any of these studies.</p><p>Methods</p><p>We applied bias-level multiple-bias analyses to two of the published narcolepsy studies: a pediatric cohort study from Finland and a case-control study from France. In particular, we developed Monte Carlo simulation models to evaluate a potential cascade of biases, including confounding by age, by indication and by natural H1N1 infection, selection bias, disease- and exposure misclassification. All bias parameters were evidence-based to the extent possible.</p><p>Results</p><p>Given the assumptions used for confounding, selection bias and misclassification, the Finnish rate ratio of 13.78 (95% CI: 5.72–28.11) reduced to a median value of 6.06 (2.5^th- 97.5^th percentile: 2.49–15.1) and the French odds ratio of 5.43 (95% CI: 2.6–10.08) to 1.85 (2.5^th—97.5^th percentile: 0.85–4.08).</p><p>Conclusion</p><p>We illustrate multiple-bias analyses using two studies on the <i>Pandemrix</i>^™-narcolepsy association and advocate their use to better understand the robustness of study findings. Based on our multiple-bias models, the observed <i>Pandemrix</i>^™-narcolepsy association consistently persists in the Finnish study. For the French study, the results of our multiple-bias models were inconclusive.</p></div

Summary of observational single-country studies on narcolepsy following vaccination with <i>Pandemrix</i>^™.

<p>Summary of observational single-country studies on narcolepsy following vaccination with <i>Pandemrix</i>^™.</p

Results of the Monte Carlo Based Multiple-bias Analyses of the Finnish Pediatric Cohort Study [16] and the French Case-Control Study [13], continued.

<p>Results of the Monte Carlo Based Multiple-bias Analyses of the Finnish Pediatric Cohort Study [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149289#pone.0149289.ref016" target="_blank">16</a>] and the French Case-Control Study [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149289#pone.0149289.ref013" target="_blank">13</a>], continued.</p