Genetic determinants of cortical structure (thickness, surface area and volumes) among disease free adults in the CHARGE Consortium

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging

The medical science DMZ: a network design pattern for data-intensive medical science

Abstract: Objective We describe a detailed solution for maintaining high-capacity, data-intensive network flows (eg, 10, 40, 100 Gbps+) in a scientific, medical context while still adhering to security and privacy laws and regulations. Materials and Methods High-end networking, packet-filter firewalls, network intrusion-detection systems. Results We describe a “Medical Science DMZ” concept as an option for secure, high-volume transport of large, sensitive datasets between research institutions over national research networks, and give 3 detailed descriptions of implemented Medical Science DMZs. Discussion The exponentially increasing amounts of “omics” data, high-quality imaging, and other rapidly growing clinical datasets have resulted in the rise of biomedical research “Big Data.” The storage, analysis, and network resources required to process these data and integrate them into patient diagnoses and treatments have grown to scales that strain the capabilities of academic health centers. Some data are not generated locally and cannot be sustained locally, and shared data repositories such as those provided by the National Library of Medicine, the National Cancer Institute, and international partners such as the European Bioinformatics Institute are rapidly growing. The ability to store and compute using these data must therefore be addressed by a combination of local, national, and industry resources that exchange large datasets. Maintaining data-intensive flows that comply with the Health Insurance Portability and Accountability Act (HIPAA) and other regulations presents a new challenge for biomedical research. We describe a strategy that marries performance and security by borrowing from and redefining the concept of a Science DMZ, a framework that is used in physical sciences and engineering research to manage high-capacity data flows. Conclusion By implementing a Medical Science DMZ architecture, biomedical researchers can leverage the scale provided by high-performance computer and cloud storage facilities and national high-speed research networks while preserving privacy and meeting regulatory requirements

Doubly Optimized Calibrated Support Vector Machine (DOC-SVM): an algorithm for joint optimization of discrimination and calibration.

Historically, probabilistic models for decision support have focused on discrimination, e.g., minimizing the ranking error of predicted outcomes. Unfortunately, these models ignore another important aspect, calibration, which indicates the magnitude of correctness of model predictions. Using discrimination and calibration simultaneously can be helpful for many clinical decisions. We investigated tradeoffs between these goals, and developed a unified maximum-margin method to handle them jointly. Our approach called, Doubly Optimized Calibrated Support Vector Machine (DOC-SVM), concurrently optimizes two loss functions: the ridge regression loss and the hinge loss. Experiments using three breast cancer gene-expression datasets (i.e., GSE2034, GSE2990, and Chanrion's datasets) showed that our model generated more calibrated outputs when compared to other state-of-the-art models like Support Vector Machine (p=0.03, p=0.13, and p<0.001) and Logistic Regression (p=0.006, p=0.008, and p<0.001). DOC-SVM also demonstrated better discrimination (i.e., higher AUCs) when compared to Support Vector Machine (p=0.38, p=0.29, and p=0.047) and Logistic Regression (p=0.38, p=0.04, and p<0.0001). DOC-SVM produced a model that was better calibrated without sacrificing discrimination, and hence may be helpful in clinical decision making