The World Health Organization’s declaration of a pandemic of the novel influenza A/H1N1 virus raises questions about the potential morbidity and mortality. By 10 July 2009, nearly 100 000 cases had been reported worldwide; however, most deaths (429 in total) have been reported in the American continents (the US, Mexico, Argentina, and Canada), with smaller numbers in other countries including the United Kingdom.1 At first sight, the data seem to imply that this new virus is relatively mild, with case fatality ratios around 0.5%, similar to the upper range of that seen for seasonal influenza2 and relatively low hospitalisation ratios. However, the case fatality ratio seems to vary substantially between countries, and deaths have occurred in much younger people than is the case for seasonal influenza.3 4

There are many reasons why simple interpretations of these crude figures at the beginning of a pandemic may be misleading both in terms of assessing severity and in making comparisons between countries. Here, we discuss some of the important mechanisms resulting in biases, propose study designs and associated statistical methods to estimate the case fatality ratio given these limitations, and show their strengths using simulated data. The two main sources of bias in estimates of the case fatality ratio we consider stem from shifts in case ascertainment (over time, efforts may become more focused on the most severe cases, leading to an overestimation of the case fatality ratio) and from the inevitable delay between symptom onset and death, which in the early phase of the epidemic can lead to underestimation of the …