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Predicting protein function and other biomedical characteristics with heterogeneous ensembles.

ABSTRACT: Prediction problems in biomedical sciences, including protein function prediction (PFP), are generally quite difficult. This is due in part to incomplete knowledge of the cellular phenomenon of interest, the appropriateness and data quality of the variables and measurements used for prediction, as well as a lack of consensus regarding the ideal predictor for specific problems. In such scenarios, a powerful approach to improving prediction performance is to construct heterogeneous ensemble predictors that combine the output of diverse individual predictors that capture complementary aspects of the problems and/or datasets. In this paper, we demonstrate the potential of such heterogeneous ensembles, derived from stacking and ensemble selection methods, for addressing PFP and other similar biomedical prediction problems. Deeper analysis of these results shows that the superior predictive ability of these methods, especially stacking, can be attributed to their attention to the following aspects of the ensemble learning process: (i) better balance of diversity and performance, (ii) more effective calibration of outputs and (iii) more robust incorporation of additional base predictors. Finally, to make the effective application of heterogeneous ensembles to large complex datasets (big data) feasible, we present DataSink, a distributed ensemble learning framework, and demonstrate its sound scalability using the examined datasets. DataSink is publicly available from https://github.com/shwhalen/datasink.

SUBMITTER: Whalen S

PROVIDER: S-EPMC4718788 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Predicting protein function and other biomedical characteristics with heterogeneous ensembles.

Whalen Sean S Pandey Om Prakash OP Pandey Gaurav G

Methods (San Diego, Calif.) 20150902

Prediction problems in biomedical sciences, including protein function prediction (PFP), are generally quite difficult. This is due in part to incomplete knowledge of the cellular phenomenon of interest, the appropriateness and data quality of the variables and measurements used for prediction, as well as a lack of consensus regarding the ideal predictor for specific problems. In such scenarios, a powerful approach to improving prediction performance is to construct heterogeneous ensemble predic ...[more]

PMID: 26342255

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Project description:Despite the importance of intracellular signaling networks, there is currently no consensus regarding the fundamental nature of the protein complexes such networks employ. One prominent view involves stable signaling machines with well-defined quaternary structures. The combinatorial complexity of signaling networks has led to an opposing perspective, namely that signaling proceeds via heterogeneous pleiomorphic ensembles of transient complexes. Since many hypotheses regarding network function rely on how we conceptualize signaling complexes, resolving this issue is a central problem in systems biology. Unfortunately, direct experimental characterization of these complexes has proven technologically difficult, while combinatorial complexity has prevented traditional modeling methods from approaching this question. Here we employ rule-based modeling, a technique that overcomes these limitations, to construct a model of the yeast pheromone signaling network. We found that this model exhibits significant ensemble character while generating reliable responses that match experimental observations. To contrast the ensemble behavior, we constructed a model that employs hierarchical assembly pathways to produce scaffold-based signaling machines. We found that this machine model could not replicate the experimentally observed combinatorial inhibition that arises when the scaffold is overexpressed. This finding provides evidence against the hierarchical assembly of machines in the pheromone signaling network and suggests that machines and ensembles may serve distinct purposes in vivo. In some cases, e.g. core enzymatic activities like protein synthesis and degradation, machines assembled via hierarchical energy landscapes may provide functional stability for the cell. In other cases, such as signaling, ensembles may represent a form of weak linkage, facilitating variation and plasticity in network evolution. The capacity of ensembles to signal effectively will ultimately shape how we conceptualize the function, evolution and engineering of signaling networks.

Project description:MotivationIntegrating multimodal data represents an effective approach to predicting biomedical characteristics, such as protein functions and disease outcomes. However, existing data integration approaches do not sufficiently address the heterogeneous semantics of multimodal data. In particular, early and intermediate approaches that rely on a uniform integrated representation reinforce the consensus among the modalities but may lose exclusive local information. The alternative late integration approach that can address this challenge has not been systematically studied for biomedical problems.ResultsWe propose Ensemble Integration (EI) as a novel systematic implementation of the late integration approach. EI infers local predictive models from the individual data modalities using appropriate algorithms and uses heterogeneous ensemble algorithms to integrate these local models into a global predictive model. We also propose a novel interpretation method for EI models. We tested EI on the problems of predicting protein function from multimodal STRING data and mortality due to coronavirus disease 2019 (COVID-19) from multimodal data in electronic health records. We found that EI accomplished its goal of producing significantly more accurate predictions than each individual modality. It also performed better than several established early integration methods for each of these problems. The interpretation of a representative EI model for COVID-19 mortality prediction identified several disease-relevant features, such as laboratory test (blood urea nitrogen and calcium) and vital sign measurements (minimum oxygen saturation) and demographics (age). These results demonstrated the effectiveness of the EI framework for biomedical data integration and predictive modeling.Availability and implementationCode and data are available at https://github.com/GauravPandeyLab/ensemble_integration.Supplementary informationSupplementary data are available at Bioinformatics Advances online.

Project description:BackgroundA large number of computational methods have been proposed for predicting protein functions. The underlying techniques adopted by most of these methods revolve around predicting the functions of an unannotated protein p from already annotated proteins that have similar characteristics as p. Recent Information Extraction methods take advantage of the huge growth of biomedical literature to predict protein functions. They extract biological molecule terms that directly describe protein functions from biomedical texts. However, they consider only explicitly mentioned terms that co-occur with proteins in texts. We observe that some important biological molecule terms pertaining functional categories may implicitly co-occur with proteins in texts. Therefore, the methods that rely solely on explicitly mentioned terms in texts may miss vital functional information implicitly mentioned in the texts.ResultsTo overcome the limitations of methods that rely solely on explicitly mentioned terms in texts to predict protein functions, we propose in this paper an Information Extraction system called PL-PPF. The proposed system employs techniques for predicting the functions of proteins based on their co-occurrences with explicitly and implicitly mentioned biological molecule terms that pertain functional categories in biomedical literature. That is, PL-PPF employs a combination of statistical-based explicit term extraction techniques and logic-based implicit term extraction techniques. The statistical component of PL-PPF predicts some of the functions of a protein by extracting the explicitly mentioned functional terms that directly describe the functions of the protein from the biomedical texts associated with the protein. The logic-based component of PL-PPF predicts additional functions of the protein by inferring the functional terms that co-occur implicitly with the protein in the biomedical texts associated with it. First, the system employs its statistical-based component to extract the explicitly mentioned functional terms. Then, it employs its logic-based component to infer additional functions of the protein. Our hypothesis is that important biological molecule terms pertaining functional categories of proteins are likely to co-occur implicitly with the proteins in biomedical texts. We evaluated PL-PPF experimentally and compared it with five systems. Results revealed better prediction performance.ConclusionsThe experimental results showed that PL-PPF outperformed the other five systems. This is an indication of the effectiveness and practical viability of PL-PPF's combination of explicit and implicit techniques. We also evaluated two versions of PL-PPF: one adopting the complete techniques (i.e., adopting both the implicit and explicit techniques) and the other adopting only the explicit terms co-occurrence extraction techniques (i.e., without the inference rules for predicate logic). The experimental results showed that the complete version outperformed significantly the other version. This is attributed to the effectiveness of the rules of predicate logic to infer functional terms that co-occur implicitly with proteins in biomedical texts. A demo application of PL-PPF can be accessed through the following link: http://ecesrvr.kustar.ac.ae:8080/plppf/.

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Predicting protein function and other biomedical characteristics with heterogeneous ensembles.

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Predicting protein function and other biomedical characteristics with heterogeneous ensembles.

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