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ON THE MERITS OF VOXEL-BASED MORPHOMETRIC PATH-ANALYSIS FOR INVESTIGATING VOLUMETRIC MEDIATION OF A TOXICANT'S INFLUENCE ON COGNITIVE FUNCTION

• Shu-chih Su, Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health
• Brian S. Caffo, Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health
• Lynn E. Eberly, University of Minnesota, School of Public Health, Division of Biostatistics
• Elizabeth Garrett-Mayer, Medical University of South Carolina, Department of Biostatistics, Bioinformatics and Epidemiology, Hollings Cancer Center
• Walter F. Stewart, Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology and Geisinger Clinic, Geisinger Center for Health Research
• Sining Chen, Johns Hopkins Bloomberg School of Public Health, Department of Environmental Health Sciences
• David Yousem, Johns Hopkins School of Medicine, The Russell H. Morgan Department of Radiology and Radiological Sciences
• Christos Davatzikos, University of Pennsylvania School of Medicine, Department of Radiology
• Brian Schwartz, Johns Hopkins Bloomberg School of Public Health, Departments of Environmental Health Sciences and Epidemiology; Johns Hopkins School of Medicine, Department of Medicine

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Abstract:

We previously showed that lifetime cumulative lead dose, measured as lead concentration in the tibia bone by X-ray fluorescence, was associated with persistent and progressive declines in cognitive function and with decreases in MRI-based brain volumes in former lead workers. Moreover, larger region-specific brain volumes were associated with better cognitive function. These findings motivated us to explore a novel application of path analysis to evaluate effect mediation. Voxel-wise path analysis, at face value, represents the natural evolution of voxel-based morphometry methods to answer questions of mediation. Application of these methods to the former lead worker data demonstrated potential limitations in this approach where there was a tendency for results to be strongly biased towards the null hypothesis (lack of mediation). Moreover, a complimentary analysis using anatomically-derived regions of interest volumes yielded opposing results, suggesting evidence of mediation. Specifically, in the ROI-based approach, there was evidence that the association of tibia lead with function in three cognitive domains was mediated through the volumes of total brain, frontal gray matter, and/or possibly cingulate. A simulation study was conducted to investigate whether the voxel-wise results arose from an absence of localized mediation, or more subtle defects in the methodology. The simulation results showed the same null bias evidenced as seen in the lead workers data. Both the lead worker data results and the simulation study suggest that a null-bias in voxel-wise path analysis limits its inferential utility for producing confirmatory results.

Subject Area:

Multivariate Analysis

Suggested Citation:

Shu-chih Su, Brian S. Caffo, Lynn E. Eberly, Elizabeth Garrett-Mayer, Walter F. Stewart, Sining Chen, David Yousem, Christos Davatzikos, and Brian Schwartz, "ON THE MERITS OF VOXEL-BASED MORPHOMETRIC PATH-ANALYSIS FOR INVESTIGATING VOLUMETRIC MEDIATION OF A TOXICANT'S INFLUENCE ON COGNITIVE FUNCTION" (January 2008). Johns Hopkins University, Dept. of Biostatistics Working Papers. Working Paper 160.
http://www.bepress.com/jhubiostat/paper160