title: Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology.
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.
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University, 350 West Lake Street, Fort Collins, CO 80521 USA ; Cardno ChemRisk, 4840 Pearl East Circle, Suite 300 West, Boulder, CO 80301 USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Fedak
authors.affiliation: Cardno ChemRisk, 130 Vantis Suite 170, Aliso Viejo, CA 92656 USA.
authors.forename: Autumn
authors.initials: A
authors.lastname: Bernal
authors.affiliation: Cardno ChemRisk, 4840 Pearl East Circle, Suite 300 West, Boulder, CO 80301 USA.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Capshaw
authors.affiliation: Cardno ChemRisk, 4840 Pearl East Circle, Suite 300 West, Boulder, CO 80301 USA.
authors.forename: Sherilyn
authors.initials: S
authors.lastname: Gross
keywords: Bradford Hill; Causal inference; Causation; Data integration; Molecular epidemiology