Effects of misclassification of causes of death on the power of a trial to assess the efficacy of a pneumococcal conjugate vaccine in The Gambia.

BACKGROUND: A reduction in cause-specific mortality may be the most important public health measure of the efficacy of a new vaccine. However, in developing countries, assignment of causes of deaths occurring outside hospitals can be assessed often only through the questioning of relatives about the signs and symptoms leading to death ('post-mortem questionnaire'). Causes assigned in this way have poor sensitivity and specificity. We illustrate the effects of this misclassification on the power of a large trial of a pneumococcal polysaccharide/protein conjugate vaccine with a mortality endpoint. METHODS: Required sample sizes to achieve a study with specified power were calculated for all-cause and acute lower respiratory tract infection (ALRI) mortality for different levels of sensitivity and specificity of post-mortem questionnaires. Data from active community-based surveillance and post-mortem questionnaires collected 1989-1993 from the study area were used in the calculations. FINDINGS: The mortality rate among children aged 6-29 months from all causes was 34.2 per 1000 child-years; 19% of deaths were attributable to ALRI. Assuming that pneumococci would be responsible for 50% of ALRI deaths and that the vaccine would cover 70% of disease serotypes and would be 90% effective against these serotypes, the expected efficacy of the vaccine would be 6.0% (19% x 50% x 70% x 90%) against all causes combined and 31.5% (50% x 70% x 90%) against deaths from ALRI. If, as suggested by various reports, the sensitivity and specificity of assigning a death to ALRI by post-mortem questionnaire are about 40% and 90% respectively, then the observed vaccine efficacy against ALRI (as classified using the post-mortem questionnaire) would fall to 20%, and the power to detect this would be reduced by approximately 40%. Furthermore, low sensitivity of diagnosis would lead to a falsely low estimate of the burden of ALRI mortality in the population and the trial might have greater power to detect a reduction in mortality from all causes combined than that estimated at the outset. CONCLUSIONS: Low sensitivity and specificity of diagnosis by post-mortem questionnaire may mean that the power of a trial to detect a reduction in all-cause mortality is similar to that to detect a reduction in ALRI mortality. Since the latter is more susceptible to bias from misclassification of cause of death, all-cause mortality may be the most suitable endpoint. Similar considerations apply to trials of interventions against other diseases for which a cause-specific endpoint is subject to substantial misclassification.