Evolutionary computing driven search based software testing and correction

For a given program, testing, locating the errors identified, and correcting those errors is a critical, yet expensive process. The field of Search Based Software Engineering (SBSE) addresses these phases by formulating them as search problems. This dissertation addresses these challenging problems through the use of two complimentary evolutionary computing based systems. The first one is the Fitness Guided Fault Localization (FGFL) system, which novelly uses a specification based fitness function to perform fault localization. The second is the Coevolutionary Automated Software Correction (CASC) system, which employs a variety of evolutionary computing techniques to perform testing, correction, and verification of software. In support of the real world application of these systems, a practitioner\u27s guide to fitness function design is provided. For the FGFL system, experimental results are presented that demonstrate the applicability of fitness guided fault localization to automate this important phase of software correction in general, and the potential of the FGFL system in particular. For the fitness function design guide, the performance of a guide generated fitness function is compared to that of an expert designed fitness function demonstrating the competitiveness of the guide generated fitness function. For the CASC system, results are presented that demonstrate the system\u27s abilities on a series of problems of both increasing size as well as number of bugs present. The system presented solutions more than 90% of the time for versions of the programs containing one or two bugs. Additionally, scalability results are presented for the CASC system that indicate that success rate linearly decreases with problem size and that the estimated convergence rate scales at worst linearly with problem size --Abstract, page ii

Co-evolutionary automated software correction: a proof of concept

The task of ensuring that a software artifact is correct can be a very time consuming process. To be able to say that an algorithm is correct is to say that it will produce results in accordance with its specifications for all valid input. One possible way to identify an incorrect implementation is through the use of automated testing (currently an open problem in the field of software engineering); however, actually correcting the implementation is typically a manual task for the software developer. In this thesis a system is presented which automates not only the testing but also the correction of an implementation. This is done using genetic programming methods to evolve the implementation itself and an appropriate evolutionary algorithm to evolve test cases. These two evolutionary algorithms are tied together using co-evolution such that each population plays a large role in the evolution of the other population. A prototype of the Co-evolutionary Automated Software Correction (CASC) system has been developed, which has allowed for preliminary experimentation to test the validity of the idea behind the CASC system --Abstract, page iii

Light-Element Abundance Variations at Low Metallicity: the Globular Cluster NGC 5466

We present low-resolution (R~850) spectra for 67 asymptotic giant branch (AGB), horizontal branch and red giant branch (RGB) stars in the low-metallicity globular cluster NGC 5466, taken with the VIRUS-P integral-field spectrograph at the 2.7-m Harlan J. Smith telescope at McDonald Observatory. Sixty-six stars are confirmed, and one rejected, as cluster members based on radial velocity, which we measure to an accuracy of 16 km s-1 via template-matching techniques. CN and CH band strengths have been measured for 29 RGB and AGB stars in NGC 5466, and the band strength indices measured from VIRUS-P data show close agreement with those measured from Keck/LRIS spectra previously taken of five of our target stars. We also determine carbon abundances from comparisons with synthetic spectra. The RGB stars in our data set cover a range in absolute V magnitude from +2 to -3, which permits us to study the rate of carbon depletion on the giant branch as well as the point of its onset. The data show a clear decline in carbon abundance with rising luminosity above the luminosity function "bump" on the giant branch, and also a subdued range in CN band strength, suggesting ongoing internal mixing in individual stars but minor or no primordial star-to-star variation in light-element abundances.Comment: 10 pages, emulateapj format, AJ accepte

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Comprehensive molecular profiling of lung adenocarcinoma: The cancer genome atlas research network

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis