High-dimensional causal mediation analysis by partial sum statistic and sample splitting strategy in imaging genetics...

Area of Science:

• Biostatistics
• Genetics
• Medical Imaging

Background:

• Causal mediation analysis is crucial for understanding exposure-outcome relationships.
• High-dimensional omics and imaging data present challenges for existing mediation methods, including violated causal assumptions and difficulties in variable selection.
• Mediators are often highly correlated, complicating the identification and prioritization of significant mediators.

Purpose of the Study:

• To develop a robust framework for high-dimensional causal mediation analysis that addresses limitations of existing methods.
• To introduce a method that satisfies causal assumptions, performs interpretable variable selection, and prioritizes mediators.
• To apply the developed method to identify mediating factors in chronic obstructive pulmonary disease (COPD).

Main Methods:

• Developed the Partial Sum Statistic and Sample Splitting Strategy (PS5) framework for high-dimensional causal mediation analysis.
• PS5 incorporates a global mediation test that adheres to causal assumptions.
• An algorithm within PS5 selects and prioritizes active mediators, quantifying individual contributions.

Main Results:

• Simulations demonstrated PS5's accurate Type I error control, enhanced statistical power, and reduced bias in mediation effect estimation.
• PS5 effectively selected and prioritized mediators across various scenarios of effect size, sparsity, and correlation.
• Application to the COPDGene study revealed a significant mediating role of a right lower lung lobe region in the association between genetic risk/smoking and lung function.

Conclusions:

• PS5 offers a powerful and statistically sound approach for high-dimensional causal mediation analysis.
• The method successfully identified specific lung image regions mediating COPD development.
• Findings suggest that targeting the identified right lower lung lobe region could be a strategy to mitigate COPD severity from genetic and environmental factors.