  Investigations of infectious disease outbreaks often focus on identifying
place- and context-dependent factors responsible for emergence and spread,
resulting in phenomenological narratives ill-suited to developing generalizable
predictive and preventive measures. We contend that case-control hypothesis
testing is a more powerful framework for epidemiological investigation. The
approach, widely used in medical research, involves identifying
counterfactuals, with case-control comparisons drawn to test hypotheses about
the conditions that manifest outbreaks. Here we outline the merits of applying
a case-control framework as epidemiological study design. We first describe a
framework for iterative multidisciplinary interrogation to discover minimally
sufficient sets of factors that can lead to disease outbreaks. We then lay out
how case-control comparisons can respectively center on pathogen(s), factor(s),
or landscape(s) with vignettes focusing on pathogen transmission. Finally, we
consider how adopting case-control approaches can promote evidence-based
decision making for responding to and preventing outbreaks.
