Thermodynamic framework to assess low abundance DNA mutation detection by hybridization

The knowledge of genomic DNA variations in patient samples has a high and increasing value for human diagnostics in its broadest sense. Although many methods and sensors to detect or quantify these variations are available or under development, the number of underlying physico-chemical detection principles is limited. One of these principles is the hybridization of sample target DNA versus nucleic acid probes. We introduce a novel thermodynamics approach and develop a framework to exploit the specific detection capabilities of nucleic acid hybridization, using generic principles applicable to any platform. As a case study, we detect point mutations in the KRAS oncogene on a microarray platform. For the given platform and hybridization conditions, we demonstrate the multiplex detection capability of hybridization and assess the detection limit using thermodynamic considerations; DNA containing point mutations in a background of wild type sequences can be identified down to at least 1% relative concentration. In order to show the clinical relevance, the detection capabilities are confirmed on challenging formalin-fixed paraffin-embedded clinical tumor samples. This enzyme-free detection framework contains the accuracy and efficiency to screen for hundreds of mutations in a single run with many potential applications in molecular diagnostics and the field of personalised medicine

Inference of Population History using Coalescent HMMs: Review and Outlook

Studying how diverse human populations are related is of historical and anthropological interest, in addition to providing a realistic null model for testing for signatures of natural selection or disease associations. Furthermore, understanding the demographic histories of other species is playing an increasingly important role in conservation genetics. A number of statistical methods have been developed to infer population demographic histories using whole-genome sequence data, with recent advances focusing on allowing for more flexible modeling choices, scaling to larger data sets, and increasing statistical power. Here we review coalescent hidden Markov models, a powerful class of population genetic inference methods that can effectively utilize linkage disequilibrium information. We highlight recent advances, give advice for practitioners, point out potential pitfalls, and present possible future research directions.Comment: 12 pages, 2 figure

Test Case Purification for Improving Fault Localization

Finding and fixing bugs are time-consuming activities in software development. Spectrum-based fault localization aims to identify the faulty position in source code based on the execution trace of test cases. Failing test cases and their assertions form test oracles for the failing behavior of the system under analysis. In this paper, we propose a novel concept of spectrum driven test case purification for improving fault localization. The goal of test case purification is to separate existing test cases into small fractions (called purified test cases) and to enhance the test oracles to further localize faults. Combining with an original fault localization technique (e.g., Tarantula), test case purification results in better ranking the program statements. Our experiments on 1800 faults in six open-source Java programs show that test case purification can effectively improve existing fault localization techniques

SlowFuzz: Automated Domain-Independent Detection of Algorithmic Complexity Vulnerabilities

Algorithmic complexity vulnerabilities occur when the worst-case time/space complexity of an application is significantly higher than the respective average case for particular user-controlled inputs. When such conditions are met, an attacker can launch Denial-of-Service attacks against a vulnerable application by providing inputs that trigger the worst-case behavior. Such attacks have been known to have serious effects on production systems, take down entire websites, or lead to bypasses of Web Application Firewalls. Unfortunately, existing detection mechanisms for algorithmic complexity vulnerabilities are domain-specific and often require significant manual effort. In this paper, we design, implement, and evaluate SlowFuzz, a domain-independent framework for automatically finding algorithmic complexity vulnerabilities. SlowFuzz automatically finds inputs that trigger worst-case algorithmic behavior in the tested binary. SlowFuzz uses resource-usage-guided evolutionary search techniques to automatically find inputs that maximize computational resource utilization for a given application.Comment: ACM CCS '17, October 30-November 3, 2017, Dallas, TX, US

A survey of cost-sensitive decision tree induction algorithms

The past decade has seen a significant interest on the problem of inducing decision trees that take account of costs of misclassification and costs of acquiring the features used for decision making. This survey identifies over 50 algorithms including approaches that are direct adaptations of accuracy based methods, use genetic algorithms, use anytime methods and utilize boosting and bagging. The survey brings together these different studies and novel approaches to cost-sensitive decision tree learning, provides a useful taxonomy, a historical timeline of how the field has developed and should provide a useful reference point for future research in this field

Designing antibiotic cycling strategies by determining and understanding local adaptive landscapes

The evolution of antibiotic resistance among bacteria threatens our continued ability to treat infectious diseases. The need for sustainable strategies to cure bacterial infections has never been greater. So far, all attempts to restore susceptibility after resistance has arisen have been unsuccessful, including restrictions on prescribing [1] and antibiotic cycling [2,3]. Part of the problem may be that those efforts have implemented different classes of unrelated antibiotics, and relied on removal of resistance by random loss of resistance genes from bacterial populations (drift). Here, we show that alternating structurally similar antibiotics can restore susceptibility to antibiotics after resistance has evolved. We found that the resistance phenotypes conferred by variant alleles of the resistance gene encoding the TEM {\beta}-lactamase (blaTEM) varied greatly among 15 different {\beta}-lactam antibiotics. We captured those differences by characterizing complete adaptive landscapes for the resistance alleles blaTEM-50 and blaTEM-85, each of which differs from its ancestor blaTEM-1 by four mutations. We identified pathways through those landscapes where selection for increased resistance moved in a repeating cycle among a limited set of alleles as antibiotics were alternated. Our results showed that susceptibility to antibiotics can be sustainably renewed by cycling structurally similar antibiotics. We anticipate that these results may provide a conceptual framework for managing antibiotic resistance. This approach may also guide sustainable cycling of the drugs used to treat malaria and HIV