The purpose of this proposal is to respond to RFA-HD-17-006 by continuing a multidisciplinary research center on learning disabilities (LDs), the Texas Center for Learning Disabilities. Consistent with the goals of RFA, we focus in Years 11-16 on persistent reading difficulties in a historically underserved group, English learners (Els). We characterize the sample as a complex phenotype and evaluate variations in math and written expression, as well as ADHD behavior and language proficiency. The proposed research uses multiple methodologies from cognitive and educational science, neuroimaging, genetics, and contemporary methodologies. The central theme is that instructional response operationalizes the historically prominent component of the LD construct, “unexpected underachievement.” Instructional response must be evaluated in children broadly representative of diverse backgrounds who are persistently impaired in academic skills and respond inadequately to instruction. To establish a reliable and valid classification of LDs, and understand cognitive, linguistic, neural, and genetic influences on LDs and instructional response, individual differences in instructional response should be systematically studied from multidisciplinary perspectives. We propose 5 Projects and 4 Cores. Project 1 (Integration) continues the past 5 years of integrative research on classification issues through evaluation of actual and simulated data, but in an El sample. It synthesizes empirical literature and conducts cross-project analyses. Project 2 (Attention) evaluates behavioral and cognitive attention and related skills over time in parallel with Projects 3, 4, and 5. It also introduces a measurement study to define attention as a construct and conducts 3 design experiments on attention in LDs. Project 3 (Intervention) builds on the previous 10 years of intervention research with a two-year double-cohort randomized controlled trial addressing reading comprehension in 820 Grade 7 Els with persistent reading difficulties. Project 4 (Neuroimaging) provides multimodal structural and functional neuroimaging studies of children who respond adequately and inadequately to Project 3 interventions. Project 5 (Epigenetics) is the high risk high reward study that evaluates epigenetic changes in DNA methylation in response to intervention in 672 participants from Project 2 (Attention) and Project 3 (Intervention). Support comes from the Administration Core (A), the Engagement Core (B), the Data Management & Statistics Core (C), and the Assessment & Recruitment Core (D). Training and dissemination opportunities are embedded throughout the Center, which has produced numerous trainees and 114 publications in the past 5 years. Synergy and cohesiveness emerges from common studies of the same cohort of Els through Project 3 (Intervention), with three shared assessments of a subset of these participants and typically developing comparison children in Projects 2 (Attention), 4 (Neuroi...