Abstract

In 1965, Sir Austin Bradford Hill published nine “viewpoints” to help determine if observed epidemiologic associations are causal. Since then, the “Bradford Hill Criteria” have become the most frequently cited framework for causal inference in epidemiologic studies. However, when Hill published his causal guidelines—just 12 years after the double-helix model for DNA was first suggested and 25 years before the Human Genome Project began—disease causation was understood on a more elementary level than it is today. Advancements in genetics, molecular biology, toxicology, exposure science, and statistics have increased our analytical capabilities for exploring potential cause-and-effect relationships, and have resulted in a greater understanding of the complexity behind human disease onset and progression. These additional tools for causal inference necessitate a re-evaluation of how each Bradford Hill criterion should be interpreted when considering a variety of data types beyond classic epidemiology studies. Herein, we explore the implications of data integration on the interpretation and application of the criteria. Using examples of recently discovered exposure–response associations in human disease, we discuss novel ways by which researchers can apply and interpret the Bradford Hill criteria when considering data gathered using modern molecular techniques, such as epigenetics, biomarkers, mechanistic toxicology, and genotoxicology.

Highlights

  • The nine “aspects of association” that Hill discussed in his address (strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy) have been used to evaluate countless hypothesized relationships between occupational and environmental exposures and disease outcomes

  • In 1965, Sir Austin Bradford Hill gave the first President’s Address to the newly formed Section on Occupational Medicine, which was published within the Proceedings of the Royal Society of Medicine [1]

  • Epidemiologic investigation of causation conducted today must evolve to reflect the concepts of data integration

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Summary

Introduction

The nine “aspects of association” that Hill discussed in his address (strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy) have been used to evaluate countless hypothesized relationships between occupational and environmental exposures and disease outcomes. By integrating results from multiple types of studies, researchers can show consistency in the causal story by illuminating various mechanistic points along the exposure-to-effects paradigm.

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