Data-driven biomarkers better associate with stroke motor outcomes than theory-based biomarkers
Authors: Olafson Emily R , Sperber Christoph , Jamison Keith W , Bowren Mark D , Boes Aaron D , Andrushko Justin W , Borich Michael R , Boyd Lara A , Cassidy Jessica M , Conforto Adriana B , Cramer Steven C , Dula Adrienne N , Geranmayeh Fatemeh , Hordacre Brenton , Jahanshad Neda , Kautz Steven A , Tavenner Bethany P , MacIntosh Bradley J , Piras Fabrizio , Robertson Andrew D , Seo Na Jin , Soekadar Surjo R , Thomopoulos Sophia I , Vecchio Daniela , Weng Timothy B , Westlye Lars T , Winstein Carolee J , Wittenberg George F , Wong Kristin A , Thompson Paul M , Liew Sook-Lei , Kuceyeski Amy F 
Published: July 2024

Abstract
Chronic motor impairments are a leading cause of disability after stroke. Previous studies have associated motor outcomes with the degree of damage to predefined structures in the motor system, such as the corticospinal tract. However, such theory-based approaches may not take full advantage of the information contained in clinical imaging data. The present study uses data-driven approaches to model chronic motor outcomes after stroke and compares the accuracy of these associations to previously-identified theory-based biomarkers. Using a cross-validation framework, regression models were trained using lesion masks and motor outcomes data from 789 stroke patients from the Enhancing NeuroImaging Genetics through Meta Analysis (ENIGMA) Stroke Recovery Working Group. Using the explained variance metric to measure the strength of the association between chronic motor outcomes and imaging biomarkers, we compared theory-based biomarkers, like lesion load to known motor tracts, to three data-driven biomarkers: lesion load of lesion-behaviour maps, lesion load of structural networks associated with lesion-behaviour maps, and measures of regional structural disconnection. In general, data-driven biomarkers had stronger associations with chronic motor outcomes accuracy than theory-based biomarkers. Data-driven models of regional structural disconnection performed the best of all models tested (R2 = 0.210, P &lt; 0.001), performing significantly better than the theory-based biomarkers of lesion load of the corticospinal tract (R2 = 0.132, P &lt; 0.001) and of multiple descending motor tracts (R2 = 0.180, P &lt; 0.001). They also performed slightly, but significantly, better than other data-driven biomarkers including lesion load of lesion-behaviour maps (R2 = 0.200, P &lt; 0.001) and lesion load of structural networks associated with lesion-behaviour maps (R2 = 0.167, P &lt; 0.001). Ensemble models - combining basic demographic variables like age, sex, and time since stroke - improved the strength of associations for theory-based and data-driven biomarkers. Combining both theory-based and data-driven biomarkers with demographic variables improved predictions, and the best ensemble model achieved R2 = 0.241, P &lt; 0.001. Overall, these results demonstrate that out-of-sample associations between chronic motor outcomes and data-driven imaging features, particularly when lesion data is represented in terms of structural disconnection, are stronger than associations between chronic motor outcomes and theory-based biomarkers. However, combining both theory-based and data-driven models provides the most robust associations.