BACKGROUND

Causal feature selection is essential for estimating effects from observational data. Identifying confounders is a crucial step in this process. Traditionally, researchers employ content-matter expertise and literature review to identify confounders. Uncontrolled confounding from unidentified confounders threatens validity, conditioning on intermediate variables (mediators) weakens estimates, and conditioning on common effects (colliders) induces bias. Additionally, without special treatment, erroneous conditioning on variables combining roles introduces bias. However, the vast literature is growing exponentially, making it infeasible to assimilate this knowledge. To address these challenges, we introduce a novel knowledge graph (KG) application enabling causal feature selection by combining computable literature-derived knowledge with biomedical ontologies. We present a use case of our approach specifying a causal model for estimating the total causal effect of depression on the risk of developing Alzheimer's disease (AD) from observational data.

METHODS

We extracted computable knowledge from a literature corpus using three machine reading systems and inferred missing knowledge using logical closure operations. Using a KG framework, we mapped the output to target terminologies and combined it with ontology-grounded resources. We translated epidemiological definitions of confounder, collider, and mediator into queries for searching the KG and summarized the roles played by the identified variables. We compared the results with output from a complementary method and published observational studies and examined a selection of confounding and combined role variables in-depth.

RESULTS

Our search identified 128 confounders, including 58 phenotypes, 47 drugs, 35 genes, 23 collider, and 16 mediator phenotypes. However, only 31 of the 58 confounder phenotypes were found to behave exclusively as confounders, while the remaining 27 phenotypes played other roles. Obstructive sleep apnea emerged as a potential novel confounder for depression and AD. Anemia exemplified a variable playing combined roles.

CONCLUSION

Our findings suggest combining machine reading and KG could augment human expertise for causal feature selection. However, the complexity of causal feature selection for depression with AD highlights the need for standardized field-specific databases of causal variables. Further work is needed to optimize KG search and transform the output for human consumption.