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Articles by C Huttenhower
Total Records ( 3 ) for C Huttenhower
  C Huttenhower , M. A Hibbs , C. L Myers , A. A Caudy , D. C Hess and O. G. Troyanskaya

Motivation: Rapidly expanding repositories of highly informative genomic data have generated increasing interest in methods for protein function prediction and inference of biological networks. The successful application of supervised machine learning to these tasks requires a gold standard for protein function: a trusted set of correct examples, which can be used to assess performance through cross-validation or other statistical approaches. Since gene annotation is incomplete for even the best studied model organisms, the biological reliability of such evaluations may be called into question.

Results: We address this concern by constructing and analyzing an experimentally based gold standard through comprehensive validation of protein function predictions for mitochondrion biogenesis in Saccharomyces cerevisiae. Specifically, we determine that (i) current machine learning approaches are able to generalize and predict novel biology from an incomplete gold standard and (ii) incomplete functional annotations adversely affect the evaluation of machine learning performance. While computational approaches performed better than predicted in the face of incomplete data, relative comparison of competing approaches—even those employing the same training data—is problematic with a sparse gold standard. Incomplete knowledge causes individual methods' performances to be differentially underestimated, resulting in misleading performance evaluations. We provide a benchmark gold standard for yeast mitochondria to complement current databases and an analysis of our experimental results in the hopes of mitigating these effects in future comparative evaluations.

  C Huttenhower , E. M Haley , M. A Hibbs , V Dumeaux , D. R Barrett , H. A Coller and O. G. Troyanskaya

Human genomic data of many types are readily available, but the complexity and scale of human molecular biology make it difficult to integrate this body of data, understand it from a systems level, and apply it to the study of specific pathways or genetic disorders. An investigator could best explore a particular protein, pathway, or disease if given a functional map summarizing the data and interactions most relevant to his or her area of interest. Using a regularized Bayesian integration system, we provide maps of functional activity and interaction networks in over 200 areas of human cellular biology, each including information from ~30,000 genome-scale experiments pertaining to ~25,000 human genes. Key to these analyses is the ability to efficiently summarize this large data collection from a variety of biologically informative perspectives: prediction of protein function and functional modules, cross-talk among biological processes, and association of novel genes and pathways with known genetic disorders. In addition to providing maps of each of these areas, we also identify biological processes active in each data set. Experimental investigation of five specific genes, AP3B1, ATP6AP1, BLOC1S1, LAMP2, and RAB11A, has confirmed novel roles for these proteins in the proper initiation of macroautophagy in amino acid-starved human fibroblasts. Our functional maps can be explored using HEFalMp (Human Experimental/Functional Mapper), a web interface allowing interactive visualization and investigation of this large body of information.

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