Reverse engineering genetic networks using nonlinear saturation kinetics
- Authors: Youseph, Ahammed , Chetty, Madhu , Karmakar, Gour
- Date: 2019
- Type: Text , Journal article
- Relation: BioSystems Vol. 182, no. (2019), p. 30-41
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- Description: A gene regulatory network (GRN) represents a set of genes along with their regulatory interactions. Cellular behavior is driven by genetic level interactions. Dynamics of such systems show nonlinear saturation kinetics which can be best modeled by Michaelis-Menten (MM) and Hill equations. Although MM equation is being widely used for modeling biochemical processes, it has been applied rarely for reverse engineering GRNs. In this paper, we develop a complete framework for a novel model for GRN inference using MM kinetics. A set of coupled equations is first proposed for modeling GRNs. In the coupled model, Michaelis-Menten constant associated with regulation by a gene is made invariant irrespective of the gene being regulated. The parameter estimation of the proposed model is carried out using an evolutionary optimization method, namely, trigonometric differential evolution (TDE). Subsequently, the model is further improved and the regulations of different genes by a given gene are made distinct by allowing varying values of Michaelis-Menten constants for each regulation. Apart from making the model more relevant biologically, the improvement results in a decoupled GRN model with fast estimation of model parameters. Further, to enhance exploitation of the search, we propose a local search algorithm based on hill climbing heuristics. A novel mutation operation is also proposed to avoid population stagnation and premature convergence. Real life benchmark data sets generated in vivo are used for validating the proposed model. Further, we also analyze realistic in silico datasets generated using GeneNetweaver. The comparison of the performance of proposed model with other existing methods shows the potential of the proposed model.
Gene regulatory network inference using Michaelis-Menten kinetics
- Authors: Youseph, Ahammed , Chetty, Madhu , Karmakar, Gour
- Date: 2015
- Type: Text , Conference proceedings
- Relation: 2015 IEEE Congress on Evolutionary Computation (Cec); Sendai, Japan; 25th-28th May 2015 p. 2392-2397
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- Description: A gene regulatory network (GRN) represents a collection of genes, connected via regulatory interactions. Reverse engineering GRNs is a challenging problem in systems biology. Various models have been proposed for modeling GRNs. However, many of these models lack the capability to explain the molecular mechanisms underlying the biological process. Michaelis-Menten kinetics can be used to model the biomolecular mechanisms and is a widely used non-linear approach to represent biochemical systems. However, the model in its current form is not suitable for reverse engineering biological systems. In this paper, based on Michaelis-Menten kinetics, we develop a new model to reverse engineer GRNs. The parameter estimation is formulated as an optimization problem which is solved by adapting trigonometric differential evolution (TDE), a variant of differential evolution (DE). The model is applied for reconstructing both in silico and in vivo networks. The results are promising and as the model is fully biologically relevant, it provides a new perspective for accurate GRN inference.
Large scale modeling of genetic networks using gene knockout data
- Authors: Youseph, Ahammed , Chetty, Madhu , Karmakar, Gour
- Date: 2018
- Type: Text , Conference proceedings
- Relation: 2018 Australasian Computer Science Week Multiconference, ACSW 2018; Brisbane, Australia; 29th January-2nd February 2018; published in ACM International Conference Proceedings Series
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- Description: Gene regulatory network (GRN) represents a set of genes and their regulatory interactions. The inference of the regulatory interactions between genes is usually carried out as an optimization problem using an appropriate mathematical model and the time-series gene expression data. Among the various models proposed for GRN inference, our recently proposed Michaelis-Menten kinetics based ODE model provides a good trade-off between the computational complexity and biological relevance. This model, like other known GRN models, also uses an evolutionary algorithm for parameter estimation. Since the search space for large networks is huge, leading to a low accuracy of inference, it is important to reduce the search region for improved performance of the optimization algorithm. In this paper, we propose a classification method using gene knockout data to eliminate a large infeasible region from the optimization search area. We also propose a method for partial inference of regulations when all the regulators of a given regulated gene are unregulated genes. The proposed method is evaluated by reconstructing in silico networks of large sizes. © 2018 ACM.
Decoupled modeling of gene regulatory networks using Michaelis-Menten kinetics
- Authors: Youseph, Ahammed , Chetty, Madhu , Karmakar, Gour
- Date: 2015
- Type: Text , Conference proceedings
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- Description: A set of genes and their regulatory interactions are represented in a gene regulatory network (GRN). Since GRNs play a major role in maintaining the cellular activities, inferring these networks is significant for understanding biological processes. Among the models available for GRN reconstruction, our recently developed nonlinear model [1] using Michaelis-Menten kinetics is considered to be more biologically relevant. However, the model remains coupled in the current form making the process computationally expensive, especially for large GRNs. In this paper, we enhance the existing model leading to a decoupled form which not only speeds up the computation, but also makes the model more realistic by representing the strength of each regulatory arc by a distinct Michaelis-Menten constant. The parameter estimation is carried out using differential evolution algorithm. The model is validated by inferring two synthetic networks. Results show that while the accuracy of reconstruction is similar to the coupled model, they are achieved at a faster speed. © Springer International Publishing Switzerland 2015.
Exploiting temporal genetic correlations for enhancing regulatory network optimization
- Authors: Youseph, Ahammed , Chetty, Madhu , Karmakar, Gour
- Date: 2016
- Type: Text , Conference proceedings
- Relation: 23rd International Conference on Neural Information Processing, ICONIP 2016; Kyoto, Japan; 16th-21st October 2016; published in Neural Information Processing (Lecture Notes in Computer Science series) Vol. 9947 LNCS, p. 479-487
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- Description: Inferring gene regulatory networks (GRN) from microarray gene expression data is a highly challenging problem in computational and systems biology. To make GRN reconstruction process more accurate and faster, in this paper, we develop a technique to identify the gene having maximum in-degree in the network using the temporal correlation of gene expression profiles. The in-degree of the identified gene is estimated applying evolutionary optimization algorithm on a decoupled S-system GRN model. The value of in-degree thus obtained is set as the maximum in-degree for inference of the regulations in other genes. The simulations are carried out on in silico networks of small and medium sizes. The results show that both the prediction accuracy in terms of well known performance metrics and the computational time of the optimization process have been improved when compared with the traditional S-system model based inference. © Springer International Publishing AG 2016.
- Description: Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
PCA based population generation for genetic network optimization
- Authors: Youseph, Ahammed , Chetty, Madhu , Karmakar, Gour
- Date: 2018
- Type: Text , Journal article
- Relation: Cognitive Neurodynamics Vol. 12, no. 4 (2018), p. 417-429
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- Description: A gene regulatory network (GRN) represents a set of genes and its regulatory interactions. The inference of the regulatory interactions between genes is usually carried out using an appropriate mathematical model and the available gene expression profile. Among the various models proposed for GRN inference, our recently proposed Michaelis–Menten based ODE model provides a good trade-off between the computational complexity and biological relevance. This model, like other known GRN models, also uses an evolutionary algorithm for parameter estimation. Considering various issues associated with such population based stochastic optimization approaches (e.g. diversity, premature convergence due to local optima, accuracy, etc.), it becomes important to seed the initial population with good individuals which are closer to the optimal solution. In this paper, we exploit the inherent strength of principal component analysis (PCA) in a novel manner to initialize the population for GRN optimization. The benefit of the proposed method is validated by reconstructing in silico and in vivo networks of various sizes. For the same level of accuracy, the approach with PCA based initialization shows improved convergence speed.
Multi agent carbon trading incorporating human traits and game theory
- Authors: Tang, Long , Chetty, Madhu , Lim, Suryani
- Date: 2011
- Type: Text , Conference paper
- Relation: 18th International Conference on Neural Information Processing, ICONIP 2011; Shanghai; China; 13th to 17th November 2011; published in Neural Information Processing, (Lecture Notes in Computer Science series) Vol. 7062 (1) p.36-47
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- Description: Carbon trading scheme is being established around the world as an instrument in reducing global GHG emission. Being an emerging market, there only a few simple simulation studies related to carbon trading that have been reported. In this paper, we propose a novel carbon trading simulator capable of modeling traits of human traders in carbon markets. The model is driven by the concept of Nash equilibrium within an agent based modeling paradigm. The model is capable of implementing crucial issues such as carbon emissions, Marginal Abatement Cost Curve (MAC), and complex human trading behaviour. Experiments carried out provide insights into interaction between traders’ behaviour and how the interaction affects profitability
- Description: Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), 2011, Vol.7064 (3)
Modeling neurocognitive reaction time with gamma distribution
- Authors: Santhanagopalan, Meena , Chetty, Madhu , Foale, Cameron , Aryal, Sunil , Klein, Britt
- Date: 2018
- Type: Text , Conference proceedings
- Relation: ACSW'18 . Proceedings of the Australasian Computer Science Week Multiconference; Brisbane, QLD; January 2018; Article 28 p. 1-10
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- Description: As a broader effort to build a holistic biopsychosocial health metric, reaction time data obtained from participants undertaking neurocognitive tests have been examined using Exploratory Data Analysis (EDA) for assessing its distribution. Many of the known existing methods assume, that the reaction time data follows a Gaussian distribution and thus commonly use statistical measures such as Analysis of Variance (ANOVA) for analysis. However, it is not mandatory for the reaction time data, to necessarily follow Gaussian distribution and in many instances, it can be better modeled by other representations such as Gamma distribution. Unlike Gaussian distribution which is defined using mean and variance, the Gamma distribution is defined using shape and scale parameters which also considers higher order moments of data such as skewness and kurtosis. Generalized Linear Models (GLM), based on the family exponential distributions such as Gamma distribution, which have been used to model reaction time in other domains, have not been fully explored for modeling reaction time data in psychology domain. While limited use of Gamma distribution have been reported [5, 17, 21], for analyzing response times, their application has been somewhat ad-hoc rather than systematic. For this proposed research, we use a real life biopsychosocial dataset, generated from the 'digital health' intervention programs conducted by the Faculty of Health, Federation University, Australia. The two digital intervention programs were the 'Mindfulness' program and 'Physical Activity' program. The neurocognitive tests were carried out as part of the 'Mindfulness' program. In this paper, we investigate the participants' reaction time distributions in neurocognitive tests such as the Psychology Experiment Building Language (PEBL) Go/No-Go test [19], which is a subset of the larger biopsychosocial data set. PEBL is an open source software system for designing and running psychological experiments. Analysis of participants' reaction time in the PEBL Go/No-Go test, shows that the reaction time data are more compatible with a Gamma distribution and clearly demonstrate that these can be better modeled by Gamma distribution.
Relevance of frequency of heart-rate peaks as indicator of ‘Biological’ Stress level
- Authors: Santhanagopalan, Meena , Chetty, Madhu , Foale, Cameron , Aryal, Sunil , Klein, Britt
- Date: 2018
- Type: Text , Conference proceedings
- Relation: ICONIP 2018 International on Neural Information Processing; Siem Reap, Cambodia; 13th-16th December, 2018 p. 598-609
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- Description: The biopsychosocial (BPS) model proposes that health is best understood as a combination of bio-physiological, psychological and social determinants, and thus advocates for a far more comprehensive investigation of the relationships between ‘mind-body’ health. For this holistic analysis, we need a suitable measure to indicate participants’ ‘biological’ stress. With the advent of wearable sensor devices, health monitoring is becoming easier. In this study, we focus on bio-physiological indicators of stress, from wearable devices using the heart-rate data. The analysis of such heart-rate data presents a set of practical challenges. We review various measures currently in use for stress measurement and their relevance and significance with the wearables’ heart-rate data. In this paper, we propose to use the novel ‘peak heart-rate count’ metric to quantify level of ‘biological’ stress. Real life biometric data obtained from digital health intervention program was considered for the study. Our study indicates the significance of using frequency of ‘peak heart-rate count’ as a ‘biological’ stress measure.
Towards machine learning approach for digital-health intervention program
- Authors: Santhanagopalan, Meena , Chetty, Madhu , Foale, Cameron , Klein, Britt
- Date: 2019
- Type: Text , Journal article
- Relation: Australian Journal of Intelligent Information Processing System Vol. 15, no. 4 (2019), p. 16-24
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- Description: Digital-Health intervention (DHI) are used by health care providers to promote engagement within community. Effective assignment of participants into DHI programs helps increasing benefits from the most suitable intervention. A major challenge with the roll-out and implementation of DHI, is in assigning participants into different interventions. The use of biopsychosocial model [18] for this purpose is not wide spread, due to limited personalized interventions formed on evidence-based data-driven models. Machine learning has changed the way data extraction and interpretation works by involving automatic sets of generic methods that have replaced the traditional statistical techniques. In this paper, we propose to investigate relevance of machine learning for this purpose and is carried out by studying different non-linear classifiers and compare their prediction accuracy to evaluate their suitability. Further, as a novel contribution, real-life biopsychosocial features are used as input in this study. The results help in developing an appropriate predictive classication model to assign participants into the most suitable DHI. We analyze biopsychosocial data generated from a DHI program and study their feature characteristics using scatter plots. While scatter plots are unable to reveal the linear relationships in the data-set, the use of classifiers can successfully identify which features are suitable predictors of mental ill health.
Sib-based survival selection technique for protein structure prediction in 3D-FCC Lattice Model
- Authors: Rumana, Nazmul , Chetty, Madhu
- Date: 2014
- Type: Text , Conference paper
- Relation: 21st International Conference on Neural Information Processing, ICONIP 2014; Kuching; Malaysia; 3rd - 6th November 2014; In Neural Information Processing (Lecture Notes in Computer Science ) Vol.8835 p.470-478 p. 470-478
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- Description: Protein Structure Prediction (PSP) is a challenging optimization problem in computational biology. A large number of non-deterministic approaches such as Evolutionary Algorithms (EAs) have been have been effectively applied to a variety of fields though, in the rugged landscape of multimodal problem like PSP, it can perform unsatisfactorily, due to premature convergence. In EAs, selection plays a significant role to avoid getting trapped in local optima and also to guide the evolution towards an optimal solution. In this paper, we propose a new Sib-based survival selection strategy suitable for application in a genetic algorithm (GA) to deal with multimodal problems. The proposed strategy, inspired by the concept of crowding method, controls the flow of genetic material by pairing off the fittest offspring amongst all the sibs (offspring inheriting most of the genetic material from an ancestor) with its ancestor for survival. Furthermore, by selecting the survivors in a hybridized manner of deterministic and probabilistic selection, the method allows the exploitation of less fit solutions along with the fitter ones and thus facilitates escaping from local optima (minima in case of PSP). Experiments conducted on a set of widely used benchmark sequences for 3D-FCC HP lattice model, demonstrate the potential of the proposed method, both in terms of diversity and optimal energy in regard to various state-of-the-art selection methods.
MCMC based Bayesian inference for modelling gene networks
- Authors: Ram, Ramesh , Chetty, Madhu
- Date: 2009
- Type: Text , Conference paper
- Relation: Pattern Recognition in Bioinformatics p. 293-306
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- Description: In this paper, we apply Bayesian networks (BN) to infer gene regulatory network (GRN) model from gene expression data. This inference process, consisting of structure search and conditional probability estimation, is challenging due to the size and quality of the data that is currently available. Our previous studies for GRN reconstruction involving evolutionary search algorithm obtained a most plausible graph structure referred as Independence-map (or simply I-map). However, the limitations of the data (large number of genes and less samples) can result in many plausible structures that equally satisfy the data set. In the present study, given the network structures, we estimate the conditional probability distribution of each variable (gene) from the data set to deduce a unique minimal I-map. This is achieved by using Markov Chain Monte Carlo (MCMC) method whereby the search space is iteratively reduced resulting in the required convergence within a reasonable computation time. We present empirical results on both, the synthetic and real-life data sets and also compare our approach with the plain MCMC sampling approach. The inferred minimal I-map on the real-life yeast data set is also presented.
Generating synthetic gene regulatory networks
- Authors: Ram, Ramesh , Chetty, Madhu
- Date: 2008
- Type: Text , Conference paper
- Relation: Third IAPR International Conference, PRIB
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- Description: Reconstructing GRN from microarray dataset is a very challenging problem as these datasets typically have large number of genes and less number of samples. Moreover, the reconstruction task becomes further complicated as there are no suitable synthetic datasets available for validation and evaluation of GRN reconstruction techniques. Synthetic datasets allow validating new techniques and approaches since the underlying mechanisms of the GRNs, generated from these datasets, are completely known. In this paper, we present an approach for synthetically generating gene networks using causal relationships. The synthetic networks can have varying topologies such as small world, random, scale free, or hierarchical topologies based on the well-defined GRN properties. These artificial but realistic GRN networks provide a simulation environment similar to a real-life laboratory microarray experiment. These networks also provide a mechanism for studying the robustness of reconstruction methods to individual and combination of parametric changes such as topology, noise (background and experimental noise) and time delays. Studies involving complicated interactions such as feedback loops, oscillations, bi-stability, dynamic behavior, vertex in-degree changes and number of samples can also be carried out by the proposed synthetic GRN networks.
Constraint minimization for efficient modelling of gene regulatory network
- Authors: Ram, Ramesh , Chetty, Madhu , Bulach, Dieter
- Date: 2008
- Type: Text , Conference paper
- Relation: Third IAPR International Conference, PRIB 2008 Melbourne
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- Description: Due to various complexities, as well as noise and high dimensionality, reconstructing a gene regulatory network (GRN) from a high-throughput microarray data becomes computationally intensive.In our earlier work on causal model approach for GRN reconstruction, we had shown the superiority of Markov blanket (MB) algorithm compared to the algorithm using the existing Y and V causal models. In this paper, we show the MB algorithm can be enhanced further by application of the proposed constraint logic minimization (CLM) technique. We describe a framework for minimizing the constraint logic involved (condition independent tests) by exploiting the Markov blanket learning methods developed for a Bayesian network (BN). The constraint relationships are represented in the form of logic using K-map and with the aid of CLM increase the algorithm efficiency and the accuracy. We show improved results by investigations on both the synthetic as well as the real life yeast cell cycle data sets.
A Markov-blanket-based model for gene regulatory network inference
- Authors: Ram, Ramesh , Chetty, Madhu
- Date: 2011
- Type: Text , Journal article
- Relation: Transactions on Computational Biology and Bioinformatics Vol. 8, no. 2 (2011), p.
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- Description: An efficient two-step Markov blanket method for modeling and inferring complex regulatory networks from large-scale microarray data sets is presented. The inferred gene regulatory network (GRN) is based on the time series gene expression data capturing the underlying gene interactions. For constructing a highly accurate GRN, the proposed method performs: 1) discovery of a gene's Markov Blanket (MB), 2) formulation of a flexible measure to determine the network's quality, 3) efficient searching with the aid of a guided genetic algorithm, and 4) pruning to obtain a minimal set of correct interactions. Investigations are carried out using both synthetic as well as yeast cell cycle gene expression data sets. The realistic synthetic data sets validate the robustness of the method by varying topology, sample size, time delay, noise, vertex in-degree, and the presence of hidden nodes. It is shown that the proposed approach has excellent inferential capabilities and high accuracy even in the presence of noise. The gene network inferred from yeast cell cycle data is investigated for its biological relevance using well-known interactions, sequence analysis, motif patterns, and GO data. Further, novel interactions are predicted for the unknown genes of the network and their influence on other genes is also discussed.
Modelling gene regulatory networks using computational intelligence techniques
- Authors: Ram, Ramesh , Chetty, Madhu
- Date: 2010
- Type: Text , Book chapter
- Relation: Handbook of Research on Computational Methodologies in Gene Regulatory Networks p. 244-265
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- Description: This chapter presents modelling gene regulatory networks (GRNs) using probabilistic causal model and the guided genetic algorithm. The problem of modelling is explained from both a biological and computational perspective. Further, a comprehensive methodology for developing a GRN model is presented where the application of computation intelligence (CI) techniques can be seen to be significantly important in each phase of modelling. An illustrative example of the causal model for GRN modelling is also included and applied to model the yeast cell cycle dataset. The results obtained are compared for providing biological relevance to the findings which thereby underpins the CI based modelling techniques.
Frequency decomposition based gene clustering
- Authors: Rahman, Md Abdur , Chetty, Madhu , Bulach, Dieter , Wangikar, Pramod
- Date: 2015
- Type: Text , Conference paper
- Relation: 22nd International Conference on Neural Information Processing, ICONIP 2015; Istanbul, Turkey; 9th-12th November 2015 Vol. 9490, p. 170-181
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- Description: Gene expressions have been commonly applied to understand the inherent underlying mechanism of known biological processes. Although the microarray gene expressions usually appear aperiodic, with proper signal processing techniques, its periodic components can be easily obtained. Thus, if expressions of interconnected (regulatory and regulated) genes are decomposed, at least one common frequency component will appear in these genes. Exploiting this novel concept, we propose a frequency decomposition approach for gene clustering to better understand the gene interconnection topology. This method, based on Hilbert Huang Transform (HHT) enables us to segregate every periodic component of the gene expressions. Next, a multilevel clustering is performed based on these frequency components. Unlike existing clustering algorithms, the proposed method assimilates a meaningful knowledge of the gene interactions topology. The information related to underlying gene interactions is vital and can prove useful in many existing evolutionary optimisation algorithms for genetic network reconstruction. We validate the entire approach by its application to a 15-gene synthetic network. © Springer International Publishing Switzerland 2015.
A study on the importance of differential prioritization in feature selection using toy datasets
- Authors: Ooi, Chia , Teng, Shyh , Chetty, Madhu
- Date: 2008
- Type: Text , Conference paper
- Relation: Third IAPR International Conference, PRIB
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- Description: Previous empirical works have shown the effectiveness of differential prioritization in feature selection prior to molecular classification. We now propose to determine the theoretical basis for the concept of differential prioritization through mathematical analyses of the characteristics of predictor sets found using different values of the DDP (degree of differential prioritization) from realistic toy datasets. Mathematical analyses based on analytical measures such as distance between classes are implemented on these predictor sets. We demonstrate that the optimal value of the DDP is capable of forming a predictor set which consists of classes of features which are well separated and are highly correlated to the target classes – a characteristic of a truly optimal predictor set. From these analyses, the necessity of adjusting the DDP based on the dataset of interest is confirmed in a mathematical manner, indicating that the DDP-based feature selection technique is superior to both simplistic rank-based selection and state-of-the-art equal-priorities scoring methods. Applying similar analyses to real-life multiclass microarray datasets, we obtain further proof of the theoretical significance of the DDP for practical applications
Degree of differential prioritization
- Authors: Ooi, Chia , Chetty, Madhu , Teng, Shyh
- Date: 2009
- Type: Journal article
- Relation: IEEE Engineering in Medicine and Biology Magazine Vol. 28, no. 4 (2009), p. 45-51
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- Description: Because of the high dimensionality of the microarray data sets, feature selection (FS) has become an important challenge in molecular classification. Using the degree of differential prioritization (DDP) between relevance and antiredundancy, our proposed DDP-based FS technique is capable of achieving better accuracies than those previously reported, using a smaller predictor set. However, previously, we have neither devised nor used any method for determining the value of the DDP to be used for the data set of interest before the FS process. In this article, we propose a system for predicting the optimal value of the DDP, which costs less computationally than conventional tuning while maintaining the independence of the FS technique from the type of underlying classifier used
Data discretization for dynamic Bayesian network based modeling of genetic networks
- Authors: Nguyen, Vinh , Chetty, Madhu , Coppel, Ross , Wangikar, Pramod
- Date: 2012
- Type: Text , Conference paper
- Relation: Neural Information Processing 19th International Conference p. 298-306
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- Description: Dynamic Bayesian networks (DBN) are widely applied in Systems biology for modeling various biological networks, including gene regulatory networks and metabolic networks. The application of DBN models often requires data discretization. Although various discretization techniques exist, currently there is no consensus on which approach is most suitable. Popular discretization strategies within the bioinformatics community, such as interval and quantile discretization, are likely not optimal. In this paper, we propose a novel approach for data discretization for mutual information based learning of DBN. In this approach, the data are discretized so that the mutual information between parent and child nodes is maximized, subject to a suitable penalty put on the complexity of the discretization. A dynamic programming approach is used to find the optimal discretization threshold for each individual variable. Our approach iteratively learns both the network and the discretization scheme until a locally optimal solution is reached. Tests on real genetic networks confirm the effectiveness of the proposed method.