Doctor of Philosophy, Texas A&M University College Station (2016)
Master of Applied Science(s), McMaster University (2012)
Bachelor of Science, University Of Tehran (2010)
Ambiguous splice sites distinguish circRNA and linear splicing in the human genome.
Bioinformatics (Oxford, England)
Motivation: Identification of splice sites is critical to gene annotation and to determine which sequences control circRNA biogenesis. Full-length RNA transcripts could in principle complete annotations of introns and exons in genomes without external ontologies, i.e., ab initio. However, whether it is possible to reconstruct genomic positions where splicing occurs from full-length transcripts, even if sampled in the absence of noise, depends on the genome sequence composition. If it is not, there exist provable limits on the use of RNA-Seq to define splice locations (linear or circular) in the genome.Results: We provide a formal definition of splice site ambiguity due to the genomic sequence by introducing a definition of equivalent junction, which is the set of local genomic positions resulting in the same RNA sequence when joined through RNA splicing. We show that equivalent junctions are prevalent in diverse eukaryotic genomes and occur in 88.64% and 78.64% of annotated human splice sites in linear and circRNA junctions, respectively. The observed fractions of equivalent junctions and the frequency of many individual motifs are statistically significant when compared against the null distribution computed via simulation or closed-form. The frequency of equivalent junctions establishes a fundamental limit on the possibility of ab initio reconstruction of RNA transcripts without appealing to the ontology of "GT-AG" boundaries defining introns. Said differently, completely ab initio is impossible in the vast majority of splice sites in annotated circRNAs and linear transcripts.Availability: Two python scripts generating an equivalent junction sequence per junction are available at: https://github.com/salzmanlab/Equivalent-Junctions.Supplementary information: Supplementary data are available at Bioinformatics online.
View details for DOI 10.1093/bioinformatics/bty785
View details for PubMedID 30192918
Efficient experimental design for uncertainty reduction in gene regulatory networks
An accurate understanding of interactions among genes plays a major role in developing therapeutic intervention methods. Gene regulatory networks often contain a significant amount of uncertainty. The process of prioritizing biological experiments to reduce the uncertainty of gene regulatory networks is called experimental design. Under such a strategy, the experiments with high priority are suggested to be conducted first.The authors have already proposed an optimal experimental design method based upon the objective for modeling gene regulatory networks, such as deriving therapeutic interventions. The experimental design method utilizes the concept of mean objective cost of uncertainty (MOCU). MOCU quantifies the expected increase of cost resulting from uncertainty. The optimal experiment to be conducted first is the one which leads to the minimum expected remaining MOCU subsequent to the experiment. In the process, one must find the optimal intervention for every gene regulatory network compatible with the prior knowledge, which can be prohibitively expensive when the size of the network is large. In this paper, we propose a computationally efficient experimental design method. This method incorporates a network reduction scheme by introducing a novel cost function that takes into account the disruption in the ranking of potential experiments. We then estimate the approximate expected remaining MOCU at a lower computational cost using the reduced networks.Simulation results based on synthetic and real gene regulatory networks show that the proposed approximate method has close performance to that of the optimal method but at lower computational cost. The proposed approximate method also outperforms the random selection policy significantly. A MATLAB software implementing the proposed experimental design method is available at http://gsp.tamu.edu/Publications/supplementary/roozbeh15a/.
View details for DOI 10.1186/1471-2105-16-S13-S2
View details for Web of Science ID 000367879400002
View details for PubMedID 26423515
View details for PubMedCentralID PMC4597030
Optimal Experimental Design for Gene Regulatory Networks in the Presence of Uncertainty
IEEE-ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS
2015; 12 (4): 938-950
Of major interest to translational genomics is the intervention in gene regulatory networks (GRNs) to affect cell behavior; in particular, to alter pathological phenotypes. Owing to the complexity of GRNs, accurate network inference is practically challenging and GRN models often contain considerable amounts of uncertainty. Considering the cost and time required for conducting biological experiments, it is desirable to have a systematic method for prioritizing potential experiments so that an experiment can be chosen to optimally reduce network uncertainty. Moreover, from a translational perspective it is crucial that GRN uncertainty be quantified and reduced in a manner that pertains to the operational cost that it induces, such as the cost of network intervention. In this work, we utilize the concept of mean objective cost of uncertainty (MOCU) to propose a novel framework for optimal experimental design. In the proposed framework, potential experiments are prioritized based on the MOCU expected to remain after conducting the experiment. Based on this prioritization, one can select an optimal experiment with the largest potential to reduce the pertinent uncertainty present in the current network model. We demonstrate the effectiveness of the proposed method via extensive simulations based on synthetic and real gene regulatory networks.
View details for DOI 10.1109/TCBB.2014.2377733
View details for Web of Science ID 000359264900027
View details for PubMedID 26357334
Sequential Experimental Design for Optimal Structural Intervention in Gene Regulatory Networks Based on the Mean Objective Cost of Uncertainty
2018; 17: 1176935118790247
Scientists are attempting to use models of ever-increasing complexity, especially in medicine, where gene-based diseases such as cancer require better modeling of cell regulation. Complex models suffer from uncertainty and experiments are needed to reduce this uncertainty. Because experiments can be costly and time-consuming, it is desirable to determine experiments providing the most useful information. If a sequence of experiments is to be performed, experimental design is needed to determine the order. A classical approach is to maximally reduce the overall uncertainty in the model, meaning maximal entropy reduction. A recently proposed method takes into account both model uncertainty and the translational objective, for instance, optimal structural intervention in gene regulatory networks, where the aim is to alter the regulatory logic to maximally reduce the long-run likelihood of being in a cancerous state. The mean objective cost of uncertainty (MOCU) quantifies uncertainty based on the degree to which model uncertainty affects the objective. Experimental design involves choosing the experiment that yields the greatest reduction in MOCU. This article introduces finite-horizon dynamic programming for MOCU-based sequential experimental design and compares it with the greedy approach, which selects one experiment at a time without consideration of the full horizon of experiments. A salient aspect of the article is that it demonstrates the advantage of MOCU-based design over the widely used entropy-based design for both greedy and dynamic programming strategies and investigates the effect of model conditions on the comparative performances.
View details for PubMedID 30093796
- Optimal Bayesian Kalman Filtering With Prior Update IEEE TRANSACTIONS ON SIGNAL PROCESSING 2018; 66 (8): 1982–96
Intrinsically Bayesian robust Karhunen-Loève compression
2018; 144: 311-322
View details for DOI 10.1016/j.sigpro.2017.10.016
- Intrinsically Bayesian Robust Kalman Filter: An Innovation Process Approach IEEE TRANSACTIONS ON SIGNAL PROCESSING 2017; 65 (10): 2531-2546
- Optimal experimental design for materials discovery COMPUTATIONAL MATERIALS SCIENCE 2017; 129: 311-322
Optimal experimental design in the context of canonical expansions
IET Signal Processing
2017; 11 (8): 942-951
View details for DOI 10.1049/iet-spr.2017.0016
Optimal Objective-Based Experimental Design for Uncertain Dynamical Gene Networks with Experimental Error.
IEEE/ACM transactions on computational biology and bioinformatics
In systems biology, network models are often used to study interactions among cellular components, a salient aim being to develop drugs and therapeutic mechanisms to change the dynamical behavior of the network to avoid undesirable phenotypes. Owing to limited knowledge, model uncertainty is commonplace and network dynamics can be updated in different ways, thereby giving multiple dynamic trajectories, that is, dynamics uncertainty. In this manuscript, we propose an experimental design method that can effectively reduce the dynamics uncertainty and improve performance in an interaction-based network. Both dynamics uncertainty and experimental error are quantified with respect to the modeling objective, herein, therapeutic intervention. The aim of experimental design is to select among a set of candidate experiments the experiment whose outcome, when applied to the network model, maximally reduces the dynamics uncertainty pertinent to the intervention objective.
View details for PubMedID 27576263