Bayesian meta-analysis for identifying periodically expressed genes in fission yeast cell cycle

The effort to identify genes with periodic expression during the cell cycle from genome-wide microarray time series data has been ongoing for a decade. However, the lack of rigorous modeling of periodic expression as well as the lack of a comprehensive model for integrating information across genes and experiments has impaired the effort for the accurate identification of periodically expressed genes. To address the problem, we introduce a Bayesian model to integrate multiple independent microarray data sets from three recent genome-wide cell cycle studies on fission yeast. A hierarchical model was used for data integration. In order to facilitate an efficient Monte Carlo sampling from the joint posterior distribution, we develop a novel Metropolis--Hastings group move. A surprising finding from our integrated analysis is that more than 40% of the genes in fission yeast are significantly periodically expressed, greatly enhancing the reported 10--15% of the genes in the current literature. It calls for a reconsideration of the periodically expressed gene detection problem.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS300 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

The EM Algorithm and the Rise of Computational Biology

In the past decade computational biology has grown from a cottage industry with a handful of researchers to an attractive interdisciplinary field, catching the attention and imagination of many quantitatively-minded scientists. Of interest to us is the key role played by the EM algorithm during this transformation. We survey the use of the EM algorithm in a few important computational biology problems surrounding the "central dogma"; of molecular biology: from DNA to RNA and then to proteins. Topics of this article include sequence motif discovery, protein sequence alignment, population genetics, evolutionary models and mRNA expression microarray data analysis.Comment: Published in at http://dx.doi.org/10.1214/09-STS312 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Bayesian detection of embryonic gene expression onset in C. elegans

To study how a zygote develops into an embryo with different tissues, large-scale 4D confocal movies of C. elegans embryos have been produced recently by experimental biologists. However, the lack of principled statistical methods for the highly noisy data has hindered the comprehensive analysis of these data sets. We introduced a probabilistic change point model on the cell lineage tree to estimate the embryonic gene expression onset time. A Bayesian approach is used to fit the 4D confocal movies data to the model. Subsequent classification methods are used to decide a model selection threshold and further refine the expression onset time from the branch level to the specific cell time level. Extensive simulations have shown the high accuracy of our method. Its application on real data yields both previously known results and new findings.Comment: Published at http://dx.doi.org/10.1214/15-AOAS820 in the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

BOOST: A fast approach to detecting gene-gene interactions in genome-wide case-control studies

Gene-gene interactions have long been recognized to be fundamentally important to understand genetic causes of complex disease traits. At present, identifying gene-gene interactions from genome-wide case-control studies is computationally and methodologically challenging. In this paper, we introduce a simple but powerful method, named `BOolean Operation based Screening and Testing'(BOOST). To discover unknown gene-gene interactions that underlie complex diseases, BOOST allows examining all pairwise interactions in genome-wide case-control studies in a remarkably fast manner. We have carried out interaction analyses on seven data sets from the Wellcome Trust Case Control Consortium (WTCCC). Each analysis took less than 60 hours on a standard 3.0 GHz desktop with 4G memory running Windows XP system. The interaction patterns identified from the type 1 diabetes data set display significant difference from those identified from the rheumatoid arthritis data set, while both data sets share a very similar hit region in the WTCCC report. BOOST has also identified many undiscovered interactions between genes in the major histocompatibility complex (MHC) region in the type 1 diabetes data set. In the coming era of large-scale interaction mapping in genome-wide case-control studies, our method can serve as a computationally and statistically useful tool.Comment: Submitte

Flatness-aware Adversarial Attack

The transferability of adversarial examples can be exploited to launch black-box attacks. However, adversarial examples often present poor transferability. To alleviate this issue, by observing that the diversity of inputs can boost transferability, input regularization based methods are proposed, which craft adversarial examples by combining several transformed inputs. We reveal that input regularization based methods make resultant adversarial examples biased towards flat extreme regions. Inspired by this, we propose an attack called flatness-aware adversarial attack (FAA) which explicitly adds a flatness-aware regularization term in the optimization target to promote the resultant adversarial examples towards flat extreme regions. The flatness-aware regularization term involves gradients of samples around the resultant adversarial examples but optimizing gradients requires the evaluation of Hessian matrix in high-dimension spaces which generally is intractable. To address the problem, we derive an approximate solution to circumvent the construction of Hessian matrix, thereby making FAA practical and cheap. Extensive experiments show the transferability of adversarial examples crafted by FAA can be considerably boosted compared with state-of-the-art baselines

Monotone Cubic B-Splines

We present a method for fitting monotone curves using cubic B-splines with a monotonicity constraint on the coefficients. We explore different ways of enforcing this constraint and analyze their theoretical and empirical properties. We propose two algorithms for solving the spline fitting problem: one that uses standard optimization techniques and one that trains a Multi-Layer Perceptrons (MLP) generator to approximate the solutions under various settings and perturbations. The generator approach can speed up the fitting process when we need to solve the problem repeatedly, such as when constructing confidence bands using bootstrap. We evaluate our method against several existing methods, some of which do not use the monotonicity constraint, on some monotone curves with varying noise levels. We demonstrate that our method outperforms the other methods, especially in high-noise scenarios. We also apply our method to analyze the polarization-hole phenomenon during star formation in astrophysics. The source code is accessible at \texttt{\url{https://github.com/szcf-weiya/MonotoneSplines.jl}}