Multivariate Residualization in Medical Imaging Analysis.

Nuisance variables in medical imaging research are common, complicating association and prediction studies based on image data. Medical image data are typically high dimensional, often consisting of many highly correlated features. As a result, computationally efficient and robust methods to address nuisance variables are difficult to implement. By-region univariate residualization is commonly used to remove the influence of nuisance variables, as are various extensions. However, these methods neglect multivariate properties and may fail to fully remove influence related to the joint distribution of these regions. Some methods, such as functional regression and others, do consider multivariate properties when controlling for nuisance variables. However, the utility of these methods is limited for data with many image regions due to computational and model complexity. We develop a multivariate residualization method to estimate the association between the image and nuisance variable using a machine learning algorithm and then compute the orthogonal projection of each subject's image data onto this space. We illustrate this method's performance in a set of simulation studies and apply it to data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).