The design and statistical power of treatment re-infection studies of the association between pre-erythrocytic immunity and infection with Plasmodium falciparum.
BACKGROUND
Understanding the role of pre-erythrocytic immune responses to Plasmodium falciparum parasites is crucial for understanding the epidemiology of malaria. However, published studies have reported inconsistent results on the association between markers of pre-erythrocytic immunity and protection from malaria.


METHODS
The design and statistical methods of studies of pre-erythrocytic immunity were reviewed, and factors affecting the likelihood of detecting statistically significant associations were assessed. Treatment re-infection studies were simulated to estimate the effects of study size, transmission intensity, and sampling frequency on the statistical power to detect an association between markers of pre-erythrocytic immunity and protection from infection.


RESULTS
Nine of nineteen studies reviewed reported statistically significant associations between markers of pre-erythrocytic immunity and protection from infection. Studies with large numbers of participants in high-transmission settings, followed longitudinally with active detection of infection and with immune responses analysed as continuous variables, were most likely to detect statistically significant associations. Simulation of treatment re-infection studies highlights that many studies are underpowered to detect statistically significant associations, providing an explanation for the finding that only some studies report significant associations between pre-erythrocytic immune responses and protection from infection.


CONCLUSIONS
The findings of the review and model simulations are consistent with the hypothesis that pre-erythrocytic immune responses prevent P. falciparum infections, but that many studies are underpowered to consistently detect this effect.
MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London, Norfolk Place, London, UK. m.white08@imperial.ac.uk
Michael T
MT
White
Jamie T
JT
Griffin
Azra C
AC
Ghani
D004812:Epidemiologic Methods; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology / Q000276:immunology* / Q000517:prevention & control; D015233:Models, Statistical; D010963:Plasmodium falciparum / Q000276:immunology*; D012008:Recurrence