From cause and effect to causes and effects.

It is now-at least loosely-acknowledged that most health and clinical outcomes are influenced by different interacting causes. Surprisingly, medical research studies are nearly universally designed to study-usually in a binary way-the effect of a single cause. Recent experiences during the coronavirus disease 2019 pandemic brought to the forefront that most of our challenges in medicine and healthcare deal with systemic, that is, interdependent and interconnected problems. Understanding these problems defy simplistic dichotomous research methodologies. These insights demand a shift in our thinking from 'cause and effect' to 'causes and effects' since this transcends the classical way of Cartesian reductionist thinking. We require a shift to a 'causes and effects' frame so we can choose the research methodology that reflects the relationships between variables of interest-one-to-one, one-to-many, many-to-one or many-to-many. One-to-one (or cause and effect) relationships are amenable to the traditional randomized control trial design, while all others require systemic designs to understand 'causes and effects'. Researchers urgently need to re-evaluate their science models and embrace research designs that allow an exploration of the clinically obvious multiple 'causes and effects' on health and disease. Clinical examples highlight the application of various systemic research methodologies and demonstrate how 'causes and effects' explain the heterogeneity of clinical outcomes. This shift in scientific thinking will allow us to find the necessary personalized or precise clinical interventions that address the underlying reasons for the variability of clinical outcomes and will contribute to greater health equity.