Iterative Random Forests to detect predictive and stable high-order interactions

Genomics has revolutionized biology, enabling the interrogation of whole transcriptomes, genome-wide binding sites for proteins, and many other molecular processes. However, individual genomic assays measure elements that interact in vivo as components of larger molecular machines. Understanding how these high-order interactions drive gene expression presents a substantial statistical challenge. Building on Random Forests (RF), Random Intersection Trees (RITs), and through extensive, biologically inspired simulations, we developed the iterative Random Forest algorithm (iRF). iRF trains a feature-weighted ensemble of decision trees to detect stable, high-order interactions with same order of computational cost as RF. We demonstrate the utility of iRF for high-order interaction discovery in two prediction problems: enhancer activity in the early Drosophila embryo and alternative splicing of primary transcripts in human derived cell lines. In Drosophila, among the 20 pairwise transcription factor interactions iRF identifies as stable (returned in more than half of bootstrap replicates), 80% have been previously reported as physical interactions. Moreover, novel third-order interactions, e.g. between Zelda (Zld), Giant (Gt), and Twist (Twi), suggest high-order relationships that are candidates for follow-up experiments. In human-derived cells, iRF re-discovered a central role of H3K36me3 in chromatin-mediated splicing regulation, and identified novel 5th and 6th order interactions, indicative of multi-valent nucleosomes with specific roles in splicing regulation. By decoupling the order of interactions from the computational cost of identification, iRF opens new avenues of inquiry into the molecular mechanisms underlying genome biology

Global Geometric Affinity for Revealing High Fidelity Protein Interaction Network

Protein-protein interaction (PPI) network analysis presents an essential role in understanding the functional relationship among proteins in a living biological system. Despite the success of current approaches for understanding the PPI network, the large fraction of missing and spurious PPIs and a low coverage of complete PPI network are the sources of major concern. In this paper, based on the diffusion process, we propose a new concept of global geometric affinity and an accompanying computational scheme to filter the uncertain PPIs, namely, reduce the spurious PPIs and recover the missing PPIs in the network. The main concept defines a diffusion process in which all proteins simultaneously participate to define a similarity metric (global geometric affinity (GGA)) to robustly reflect the internal connectivity among proteins. The robustness of the GGA is attributed to propagating the local connectivity to a global representation of similarity among proteins in a diffusion process. The propagation process is extremely fast as only simple matrix products are required in this computation process and thus our method is geared toward applications in high-throughput PPI networks. Furthermore, we proposed two new approaches that determine the optimal geometric scale of the PPI network and the optimal threshold for assigning the PPI from the GGA matrix. Our approach is tested with three protein-protein interaction networks and performs well with significant random noises of deletions and insertions in true PPIs. Our approach has the potential to benefit biological experiments, to better characterize network data sets, and to drive new discoveries

The impact of histological annotations for accurate tissue classification using mass spectrometry imaging

Knowing the precise location of analytes in the tissue has the potential to provide information about the organs’ function and predict its behavior. It is especially powerful when used in diagnosis and prognosis prediction of pathologies, such as cancer. Spatial proteomics, in particular mass spectrometry imaging, together with machine learning approaches, has been proven to be a very helpful tool in answering some histopathology conundrums. To gain accurate information about the tissue, there is a need to build robust classification models. We have investigated the impact of histological annotation on the classification accuracy of different tumor tissues. Intrinsic tissue heterogeneity directly impacts the efficacy of the annotations, having a more pronounced effect on more heterogeneous tissues, as pancreatic ductal adenocarcinoma, where the impact is over 20% in accuracy. On the other hand, in more homogeneous samples, such as kidney tumors, histological annotations have a slenderer impact on the classification accuracy

Multi-wavelet residual dense convolutional neural network for image denoising

Networks with large receptive field (RF) have shown advanced fitting ability in recent years. In this work, we utilize the short-term residual learning method to improve the performance and robustness of networks for image denoising tasks. Here, we choose a multi-wavelet convolutional neural network (MWCNN), one of the state-of-art networks with large RF, as the backbone, and insert residual dense blocks (RDBs) in its each layer. We call this scheme multi-wavelet residual dense convolutional neural network (MWRDCNN). Compared with other RDB-based networks, it can extract more features of the object from adjacent layers, preserve the large RF, and boost the computing efficiency. Meanwhile, this approach also provides a possibility of absorbing advantages of multiple architectures in a single network without conflicts. The performance of the proposed method has been demonstrated in extensive experiments with a comparison with existing techniques.Comment: 9 pages, 9 figure

Application and Extension of Weighted Quantile Sum Regression for the Development of a Clinical Risk Prediction Tool

In clinical settings, the diagnosis of medical conditions is often aided by measurement of various serum biomarkers through the use of laboratory tests. These biomarkers provide information about different aspects of a patient’s health and the overall function of different organs. In this dissertation, we develop and validate a weighted composite index that aggregates the information from a variety of health biomarkers covering multiple organ systems. The index can be used for predicting all-cause mortality and could also be used as a holistic measure of overall physiological health status. We refer to it as the Health Status Metric (HSM). Validation analysis shows that the HSM is predictive of long-term mortality risk and exhibits a robust association with concurrent chronic conditions, recent hospital utilization, and self-rated health. We develop the HSM using Weighted Quantile Sum (WQS) regression (Gennings et al., 2013; Carrico, 2013), a novel penalized regression technique that imposes nonnegativity and unit-sum constraints on the coefficients used to weight index components. In this dissertation, we develop a number of extensions to the WQS regression technique and apply them to the construction of the HSM. We introduce a new guided approach for the standardization of index components which accounts for potential nonlinear relationships with the outcome of interest. An extended version of the WQS that accommodates interaction effects among index components is also developed and implemented. In addition, we demonstrate that ensemble learning methods borrowed from the field of machine learning can be used to improve the predictive power of the WQS index. Specifically, we show that the use of techniques such as weighted bagging, the random subspace method and stacked generalization in conjunction with the WQS model can produce an index with substantially enhanced predictive accuracy. Finally, practical applications of the HSM are explored. A comparative study is performed to evaluate the feasibility and effectiveness of a number of ‘real-time’ imputation strategies in potential software applications for computing the HSM. In addition, the efficacy of the HSM as a predictor of hospital readmission is assessed in a cohort of emergency department patients

A data analytics approach to gas turbine prognostics and health management

As a consequence of the recent deregulation in the electrical power production industry, there has been a shift in the traditional ownership of power plants and the way they are operated. To hedge their business risks, the many new private entrepreneurs enter into long-term service agreement (LTSA) with third parties for their operation and maintenance activities. As the major LTSA providers, original equipment manufacturers have invested huge amounts of money to develop preventive maintenance strategies to minimize the occurrence of costly unplanned outages resulting from failures of the equipments covered under LTSA contracts. As a matter of fact, a recent study by the Electric Power Research Institute estimates the cost benefit of preventing a failure of a General Electric 7FA or 9FA technology compressor at $10 to$20 million. Therefore, in this dissertation, a two-phase data analytics approach is proposed to use the existing monitoring gas path and vibration sensors data to first develop a proactive strategy that systematically detects and validates catastrophic failure precursors so as to avoid the failure; and secondly to estimate the residual time to failure of the unhealthy items. For the first part of this work, the time-frequency technique of the wavelet packet transforms is used to de-noise the noisy sensor data. Next, the time-series signal of each sensor is decomposed to perform a multi-resolution analysis to extract its features. After that, the probabilistic principal component analysis is applied as a data fusion technique to reduce the number of the potentially correlated multi-sensors measurement into a few uncorrelated principal components. The last step of the failure precursor detection methodology, the anomaly detection decision, is in itself a multi-stage process. The obtained principal components from the data fusion step are first combined into a one-dimensional reconstructed signal representing the overall health assessment of the monitored systems. Then, two damage indicators of the reconstructed signal are defined and monitored for defect using a statistical process control approach. Finally, the Bayesian evaluation method for hypothesis testing is applied to a computed threshold to test for deviations from the healthy band. To model the residual time to failure, the anomaly severity index and the anomaly duration index are defined as defects characteristics. Two modeling techniques are investigated for the prognostication of the survival time after an anomaly is detected: the deterministic regression approach, and parametric approximation of the non-parametric Kaplan-Meier plot estimator. It is established that the deterministic regression provides poor prediction estimation. The non parametric survival data analysis technique of the Kaplan-Meier estimator provides the empirical survivor function of the data set comprised of both non-censored and right censored data. Though powerful because no a-priori predefined lifetime distribution is made, the Kaplan-Meier result lacks the flexibility to be transplanted to other units of a given fleet. The parametric analysis of survival data is performed with two popular failure analysis distributions: the exponential distribution and the Weibull distribution. The conclusion from the parametric analysis of the Kaplan-Meier plot is that the larger the data set, the more accurate is the prognostication ability of the residual time to failure model.PhDCommittee Chair: Mavris, Dimitri; Committee Member: Jiang, Xiaomo; Committee Member: Kumar, Virendra; Committee Member: Saleh, Joseph; Committee Member: Vittal, Sameer; Committee Member: Volovoi, Vital