Links: Go to episode page (with episode resources) Subscribe to Premium Receive the Sigma Nutrition newsletter About This Episode: Numerous nutrition studies present findings of “no effect,” but interpreting such results requires caution. A null finding, indicating an absence of impact from a nutrient or exposure, may not necessarily suggest a lack of effect overall. Instead, it could stem from issues related to the study’s design, the nature of the exposure, or participant characteristics. We’ve often referred to such studies as being “null by design”. These studies, often termed “null by design,” may yield inconclusive results due to insufficient contrast in exposure levels to reveal a significant effect size. Additionally, participants’ baseline nutrient status or intake can contribute to false negatives. For instance, if a study provides a nutrient to individuals already replete in that nutrient, it may lead to an erroneous conclusion. This phenomenon can be understood by considering the bell curve of activity for a nutrient. Moreover, a lack of methodological rigor can generate ‘false negatives.’ If previous literature indicates associations between high intake of a specific food or nutrient and certain outcomes, a study comparing levels of intake well below that threshold may produce a misleading result. Some challenges arise from an overly reductionist perspective. In disease processes, reductionism simplifies diseases to a single primary source at the cellular and molecular level. This perspective assumes that if a nutrient shows a relationship with health or disease outcomes at a population level, its biological activity should manifest in isolation. However, applying such assumptions to exposures like diet may not be tenable. In this discussion, we delve into the concept of “null by design” and present three specific studies with null findings, emphasizing the need for careful interpretation.