Congenital heart disease (CHD) is the most prevalent birth defect, affecting nearly 1% of live births1, but the incidence of CHD is up to ten fold higher in human fetuses2,3. A genetic contribution is strongly suggested by the association of CHD with chromosome abnormalities and high recurrence risk4. Here we report findings from a recessive forward genetic screen in fetal mice, showing the cilium and cilia transduced cell signaling play important roles in the pathogenesis of CHD. The cilium is an evolutionarily conserved organelle projecting from the cell surface with essential roles in diverse cellular processes. Using echocardiography, we ultrasound scanned 87,355 chemically mutagenized C57BL/6J fetal mice and recovered 218 CHD mouse models. Whole exome sequencing identified 91 recessive CHD mutations in 61 genes. This included 34 cilia-related genes, 16 genes involved in cilia transduced cell signaling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signaling. Surprisingly, many CHD genes encoded interacting proteins, suggesting an interactome protein network may provide a larger genomic context for CHD pathogenesis. These findings provide novel insights into the potential Mendelian genetic contribution to CHD in the fetal population, a segment of the human population not well studied. We note pathways identified show overlap with CHD candidate genes recovered in CHD patients5, suggesting they may have relevance to the more complex genetics of CHD overall. These CHD mouse models and >8,000 incidental mutations are sperm archived, creating a rich public resource for human disease modeling.
Whereas people learn many different types of knowledge from diverse experiences over many years, and become better learners over time, most current machine learning systems are much more narrow, learning just a single function or data model based on statistical analysis of a single data set. We suggest that people learn better than computers precisely because of this difference, and we suggest a key direction for machine learning research is to develop software architectures that enable intelligent agents to also learn many types of knowledge, continuously over many years, and to become better learners over time. In this paper we define more precisely this never-ending learning paradigm for machine learning, and we present one case study: the Never-Ending Language Learner (NELL), which achieves a number of the desired properties of a never-ending learner. NELL has been learning to read the Web 24hrs/ day since January 2010, and so far has acquired a knowledge base with 120mn diverse, confidence-weighted beliefs (e.g., servedWith(tea,biscuits)), while learning thousands of interrelated functions that continually improve its reading competence over time. NELL has also learned to reason over its knowledge base to infer new beliefs it has not yet read from those it has, and NELL is inventing new relational predicates to extend the ontology it uses to represent beliefs. We describe the design of NELL, experimental results illustrating its behavior, and discuss both its successes and shortcomings as a case study in never-ending learning. NELL can be tracked online at http://rtw.ml.cmu.edu, and followed on Twitter at @CMUNELL. 2. RELATED WORK Previous research has considered the problem of designing machine learning agents that persist over long periods research highlights
Genome-wide association studies of schizophrenia (GWAS) have revealed the role of rare and common genetic variants, but the functional effects of the risk variants remain to be understood. Protein interactome-based studies can facilitate the study of molecular mechanisms by which the risk genes relate to schizophrenia (SZ) genesis, but protein–protein interactions (PPIs) are unknown for many of the liability genes. We developed a computational model to discover PPIs, which is found to be highly accurate according to computational evaluations and experimental validations of selected PPIs. We present here, 365 novel PPIs of liability genes identified by the SZ Working Group of the Psychiatric Genomics Consortium (PGC). Seventeen genes that had no previously known interactions have 57 novel interactions by our method. Among the new interactors are 19 drug targets that are targeted by 130 drugs. In addition, we computed 147 novel PPIs of 25 candidate genes investigated in the pre-GWAS era. While there is little overlap between the GWAS genes and the pre-GWAS genes, the interactomes reveal that they largely belong to the same pathways, thus reconciling the apparent disparities between the GWAS and prior gene association studies. The interactome including 504 novel PPIs overall, could motivate other systems biology studies and trials with repurposed drugs. The PPIs are made available on a webserver, called Schizo-Pi at http://severus.dbmi.pitt.edu/schizo-pi with advanced search capabilities.
BackgroundBiological processes in cells are carried out by means of protein-protein interactions. Determining whether a pair of proteins interacts by wet-lab experiments is resource-intensive; only about 38,000 interactions, out of a few hundred thousand expected interactions, are known today. Active machine learning can guide the selection of pairs of proteins for future experimental characterization in order to accelerate accurate prediction of the human protein interactome.ResultsRandom forest (RF) has previously been shown to be effective for predicting protein-protein interactions. Here, four different active learning algorithms have been devised for selection of protein pairs to be used to train the RF. With labels of as few as 500 protein-pairs selected using any of the four active learning methods described here, the classifier achieved a higher F-score (harmonic mean of Precision and Recall) than with 3000 randomly chosen protein-pairs. F-score of predicted interactions is shown to increase by about 15% with active learning in comparison to that with random selection of data.ConclusionActive learning algorithms enable learning more accurate classifiers with much lesser labelled data and prove to be useful in applications where manual annotation of data is formidable. Active learning techniques demonstrated here can also be applied to other proteomics applications such as protein structure prediction and classification.
Whereas people learn many different types of knowledge from diverse experiences over many years, most current machine learning systems acquire just a single function or data model from just a single data set. We propose a never-ending learning paradigm for machine learning, to better reflect the more ambitious and encompassing type of learning performed by humans. As a case study, we describe the Never-Ending Language Learner (NELL), which achieves some of the desired properties of a never-ending learner, and we discuss lessons learned. NELL has been learning to read the web 24 hours/day since January 2010, and so far has acquired a knowledge base with over 80 million confidence-weighted beliefs (e.g., servedWith(tea, biscuits)). NELL has also learned millions of features and parameters that enable it to read these beliefs from the web. Additionally, it has learned to reason over these beliefs to infer new beliefs, and is able to extend its ontology by synthesizing new relational predicates. NELL can be tracked online at http://rtw.ml.cmu.edu, and followed on Twitter at @CMUNELL.
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