Testing Pneumonia Vaccines in the Elderly: Determining a Case Definition for Pneumococcal Pneumonia in the Absence of a Gold Standard

Abstract

Clinical assessments of vaccines to prevent pneumococcal (Pnc) community-acquired pneumonia (CAP) require sensitive and specific case definitions, but there is no gold standard diagnostic test. To develop a new case definition suitable for vaccine efficacy studies, we applied latent class analysis (LCA) to the results from seven diagnostic tests for Pnc etiology on clinical specimens from 323 elderly radiologically-confirmed pneumonia cases enrolled in The Finnish Community-Acquired Pneumonia Epidemiology study during 2005–2007. Compared to the conventional use of LCA, which is mainly to determine sensitivities and specificities of different tests, we instead used LCA as an appropriate instrument to predict the probability of Pnc etiology for each CAP case based on their test profiles, and utilized the predictions to minimize the sample size that would be needed for a vaccine efficacy trial. When compared to the conventional laboratory criteria of encapsulated Pnc in blood culture or in high-quality sputum culture or urine antigen positivity, our optimized case definition for PncCAP resulted in a trial sample size which was almost 20,000 subjects smaller. We believe that our novel application of LCA detailed here to determine a case definition for PncCAP could also be similarly applied to other diseases without a gold standard.