Epidemics of Chikungunya, Zika, and COVID-19 Reveal Bias in Case-Based Mapping

Abstract

Background: In recent years, tropical countries have faced consecutive explosive epidemics of chikungunya, Zika, and now COVID-19, each of which have featured large proportions of subclinical infections. Spatial studies of epidemics typically use case-only datasets to estimate incidence rates (cases/total population), often misinterpreting them as infection risks (infections/total population) or disease risks (cases/infected population). Methods: We examined these three measures in a pediatric cohort (N≈3,000) over two chikungunya epidemics and one Zika epidemic and in a household cohort (N=1,793) over one COVID-19 epidemic in Nicaragua. We used generalized additive models, the intra-cluster correlation coefficient, cluster detection analyses, geostatistical models, and spatiotemporal models to characterize the spatial epidemiology of each epidemic and examine the limitations of the case-only incidence rate. Results: Across analyses and all epidemics, case-based incidence rates considerably underestimated both infection and disease risks, resulting in a high and spatially non-uniform degree of bias. The spatial infection risk differed from the spatial disease risk, showing that areas with many infections did not necessarily have many cases. Typical case-only approaches precluded a full understanding of the spatial contours of immunity. Standard incidence cluster analyses unpredictably resembled either clusters of infection or disease risk across all epidemics. Spatiotemporal modeling of disease incidence revealed less pronounced dynamics than spatiotemporal modeling of infection risk. Interpretation: During epidemics of pathogens that cause large numbers of subclinical infections, misinterpreting incidence rates, as is common, results in substantial bias, a general finding applicable to many pathogens of high human concern. Funding Information: This study was supported by grants R01 AI099631 (AB), P01 AI106695 (EH), R01 AI120997 (AG), and U19 AI118610 (EH) from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; the National Institutes of Health Centers of Excellence for Influenza Research and Surveillance [contract: HHS 272201400006C (AG)]; and the Open Philanthropy Project Fund for the production of recombinant SARS-CoV-2 spike protein, its receptor binding domain, and antibodies at the University of Michigan Center for Structural Biology. FBC was partially supported by a supplement to grant P01 AI106695. Declaration of Interests: Authors declare that they have no competing interests. Ethics Approval Statement: The Pediatric Dengue Cohort Study (PDCS) was approved by Institutional Review Boards of the University of California, Berkeley, the University of Michigan, Ann Arbor, and the Nicaraguan Ministry of Health. The Household Influenza Cohort Study (HICS) was approved by the University of Michigan, Ann Arbor and the Nicaraguan Ministry of Health. Participants’ parents or legal guardians provided written informed consent. Subjects six years and older provided verbal assent.