Testing the Tests: Using Connectome-Based Predictive Models to Reveal the Systems Standardized Tests and Clinical Symptoms are Reflecting

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Abstract
Background: Substantial strides have been made in developing connectome-based predictive models that establish connections between external measures of cognition and/or symptoms obtained through testing performed in a clinical setting, and the human functional connectome. Often referred to as brain-behavior modeling such models offer insights into the functional brain organization supporting the test scores of these external measures 1–7 . Here, we depart from the conventional feed-forward approach and introduce a feed-back approach that provides new insight into the systems the external measures are reflecting and provides a framework for developing new test instruments that better target specific brain systems. Methods: In fMRI data from 227 demographically and clinically diverse subjects (healthy participants and patients), we a priori define connectivity networks for the six cognitive constructs and employ kernel ridge regression in a predictive modeling framework to quantify each network’s contribution to performance across a spectrum of standardized tests. Results: This approach provides a ranking of test scores according to the predictive power of each cognitive network, allowing one to choose the best test to probe a specific brain network. It yields a brain-driven process for forming new tests through selection of combinations of measures that probe the same brain systems. These new composite tests yield better external measures, as reflected by higher predictive power in brain-behavior modeling. We also evaluate the inclusion of specific subtests within a composite score, revealing instances where composite scores are reinforced or weakened by subtest inclusion regarding the specificity of the brain network they interrogate. Conclusions: The brain-behavior modeling problem can be reconfigured to provide a biologically driven approach to the selection of external measures directed at specific brain systems. It opens new avenues of research by providing a framework for the development of measures, both cognitive and clinical, guided by quantitative brain metrics.

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