ABSTRACT
Vocal production learning ("vocal learning") is a convergently evolved trait in vertebrates. To identify brain genomic elements associated with mammalian vocal learning, we integrated genomic, anatomical, and neurophysiological data from the Egyptian fruit bat (Rousettus aegyptiacus) with analyses of the genomes of 215 placental mammals. First, we identified a set of proteins evolving more slowly in vocal learners. Then, we discovered a vocal motor cortical region in the Egyptian fruit bat, an emergent vocal learner, and leveraged that knowledge to identify active cis-regulatory elements in the motor cortex of vocal learners. Machine learning methods applied to motor cortex open chromatin revealed 50 enhancers robustly associated with vocal learning whose activity tended to be lower in vocal learners. Our research implicates convergent losses of motor cortex regulatory elements in mammalian vocal learning evolution.
Subject(s)
Enhancer Elements, Genetic , Eutheria , Evolution, Molecular , Gene Expression Regulation , Motor Cortex , Motor Neurons , Proteins , Vocalization, Animal , Animals , Chiroptera/genetics , Chiroptera/physiology , Vocalization, Animal/physiology , Motor Cortex/cytology , Motor Cortex/physiology , Chromatin/metabolism , Motor Neurons/physiology , Larynx/physiology , Epigenesis, Genetic , Genome , Proteins/genetics , Proteins/metabolism , Amino Acid Sequence , Eutheria/genetics , Eutheria/physiology , Machine LearningABSTRACT
BACKGROUND AND PURPOSE: Adaptive trial designs that allow enrichment of the study population through subgroup selection can increase the chance of a positive trial when there is a differential treatment effect among patient subgroups. The goal of this study is to illustrate the potential benefit of adaptive subgroup selection in endovascular stroke studies. METHODS: We simulated the performance of a trial design with adaptive subgroup selection and compared it with that of a traditional design. Outcome data were based on 90-day modified Rankin Scale scores, observed in IMS III (Interventional Management of Stroke III), among patients with a vessel occlusion on baseline computed tomographic angiography (n=382). Patients were categorized based on 2 methods: (1) according to location of the arterial occlusive lesion and onset-to-randomization time and (2) according to onset-to-randomization time alone. The power to demonstrate a treatment benefit was based on 10 000 trial simulations for each design. RESULTS: The treatment effect was relatively homogeneous across categories when patients were categorized based on arterial occlusive lesion and time. Consequently, the adaptive design had similar power (47%) compared with the fixed trial design (45%). There was a differential treatment effect when patients were categorized based on time alone, resulting in greater power with the adaptive design (82%) than with the fixed design (57%). CONCLUSIONS: These simulations, based on real-world patient data, indicate that adaptive subgroup selection has merit in endovascular stroke trials as it substantially increases power when the treatment effect differs among subgroups in a predicted pattern.
