Precision cancer monitoring using a novel, fully integrated, microfluidic array partitioning digital PCR platform.

A novel digital PCR (dPCR) platform combining off-the-shelf reagents, a micro-molded plastic microfluidic consumable with a fully integrated single dPCR instrument was developed to address the needs for routine clinical diagnostics. This new platform offers a simplified workflow that enables: rapid time-to-answer; low potential for cross contamination; minimal sample waste; all within a single integrated instrument. Here we showcase the capability of this fully integrated platform to detect and quantify non-small cell lung carcinoma (NSCLC) rare genetic mutants (EGFR T790M) with precision cell-free DNA (cfDNA) standards. Next, we validated the platform with an established chronic myeloid leukemia (CML) fusion gene (BCR-ABL1) assay down to 0.01% mutant allele frequency to highlight the platform's utility for precision cancer monitoring. Thirdly, using a juvenile myelomonocytic leukemia (JMML) patient-specific assay we demonstrate the ability to precisely track an individual cancer patient's response to therapy and show the patient's achievement of complete molecular remission. These three applications highlight the flexibility and utility of this novel fully integrated dPCR platform that has the potential to transform personalized medicine for cancer recurrence monitoring

Predictors of repair and effect of gender on treatment of ruptured abdominal aortic aneurysm

AbstractObjectiveThe purpose of this study was to determine factors associated with increased likelihood of patients undergoing surgery to repair ruptured abdominal aortic aneurysms (AAAs). Specifically, we investigated whether men were more likely than women to be selected for surgery after rupture of AAAs.MethodsAll patients with a ruptured AAA who came to a hospital in Ontario between April 1, 1992, and March 31, 2001, were included in this population-based retrospective study. Administrative data were used to identify patients, patient demographic data, and hospital variables.ResultsCrude 30-day mortality for the 3570 patients who came to a hospital with a ruptured AAA was 53.4%. Of the 2602 patients (72.9%) who underwent surgical repair, crude 30-day mortality was 41.0%. Older patients (odds ratio [OR], 0.649 per 5 years of age; P < .0001), with a higher Charlson Comorbidity Index (OR, 0.848; P < .0001), were less likely to undergo AAA repair. Patients treated at high-volume centers (OR, 2.674 per 10 cases; P < .0001) and men (OR, 2.214; P < .0001) were more likely to undergo AAA repair.ConclusionMen are more likely to undergo repair of a ruptured AAA than women are, for reasons that are unclear. Given the large magnitude of the effect, further studies are clearly indicated

Survival after ruptured abdominal aortic aneurysm: effect of patient, surgeon, and hospital factors

AbstractObjectiveThe purpose of this study was to determine the effects of patient, surgeon, and hospital factors on survival after repair of ruptured abdominal aortic aneurysm (AAA) and to compare them with risk factors for survival after elective AAA repair. It was hypothesized that patients operated on by high-volume surgeons with subspecialty training would have better outcomes, which might argue for regionalization of AAA surgery.MethodsIn this population-based retrospective cohort study, surgeon billing and administrative data were used to identify all patients who had undergone AAA repair between April 1, 1992, and March 31, 2001, in Ontario, Canada. Demographic information was collected for each patient, as well as numerous variables related to the surgeons and hospitals.ResultsThere were 2601 patients with ruptured AAA repair, with an average 30-day mortality rate of 40.8%. Significant independent predictors of lower survival were older age, female gender, lower patient income quintile, performance of surgery at night or on weekends, repair in larger cities, surgeons with lower annual volume of ruptured AAA operations, and surgeons without vascular or cardiothoracic fellowship training. There were 13,701 patients with elective AAA repair, with an average 30-day mortality rate of 4.5%. Significant independent predictors of lower survival were similar, except gender was not significant, but the Charlson Comorbidity Index was. When the hazard ratios associated with predictive factors were compared, surgeon factors appeared to be more important in ruptured AAA repair, and patient factors appeared more important in elective AAA repair.ConclusionFor elective AAA repair, and even more so for ruptured AAA repair, high-volume surgeons with subspecialty training conferred a significant survival benefit for patients. Although this would seem to argue in favor of regionalization, decisions should await a more complete understanding of the relationship between transfer time, delay in treatment, and outcome

Local search: A guide for the information retrieval practitioner

There are a number of combinatorial optimisation problems in information retrieval in which the use of local search methods are worthwhile. The purpose of this paper is to show how local search can be used to solve some well known tasks in information retrieval (IR), how previous research in the field is piecemeal, bereft of a structure and methodologically flawed, and to suggest more rigorous ways of applying local search methods to solve IR problems. We provide a query based taxonomy for analysing the use of local search in IR tasks and an overview of issues such as fitness functions, statistical significance and test collections when conducting experiments on combinatorial optimisation problems. The paper gives a guide on the pitfalls and problems for IR practitioners who wish to use local search to solve their research issues, and gives practical advice on the use of such methods. The query based taxonomy is a novel structure which can be used by the IR practitioner in order to examine the use of local search in IR

Gene set-based module discovery in the breast cancer transcriptome

<p>Abstract</p> <p>Background</p> <p>Although microarray-based studies have revealed global view of gene expression in cancer cells, we still have little knowledge about regulatory mechanisms underlying the transcriptome. Several computational methods applied to yeast data have recently succeeded in identifying expression modules, which is defined as co-expressed gene sets under common regulatory mechanisms. However, such module discovery methods are not applied cancer transcriptome data.</p> <p>Results</p> <p>In order to decode oncogenic regulatory programs in cancer cells, we developed a novel module discovery method termed EEM by extending a previously reported module discovery method, and applied it to breast cancer expression data. Starting from seed gene sets prepared based on <it>cis</it>-regulatory elements, ChIP-chip data, and gene locus information, EEM identified 10 principal expression modules in breast cancer based on their expression coherence. Moreover, EEM depicted their activity profiles, which predict regulatory programs in each subtypes of breast tumors. For example, our analysis revealed that the expression module regulated by the Polycomb repressive complex 2 (PRC2) is downregulated in triple negative breast cancers, suggesting similarity of transcriptional programs between stem cells and aggressive breast cancer cells. We also found that the activity of the PRC2 expression module is negatively correlated to the expression of EZH2, a component of PRC2 which belongs to the E2F expression module. E2F-driven EZH2 overexpression may be responsible for the repression of the PRC2 expression modules in triple negative tumors. Furthermore, our network analysis predicts regulatory circuits in breast cancer cells.</p> <p>Conclusion</p> <p>These results demonstrate that the gene set-based module discovery approach is a powerful tool to decode regulatory programs in cancer cells.</p

Prediction of outcome after abdominal aortic aneurysm rupture

BackgroundMost vascular surgeons practice a selective policy of operative intervention for patients with ruptured abdominal aortic aneurysm (AAA). The evidence on which to justify operative selection remains uncertain. This review examines the prediction of outcome after attempted open repair of ruptured AAA.MethodsThe Medline and EMBASE databases and Cochrane Database of Systematic Reviews were searched for clinical studies relating to the prediction of outcome after ruptured AAA. Reference lists of relevant articles were also reviewed.ResultsThe last 20 years has seen >60 publications considering variables predictive of outcome after AAA rupture. Four predictive scoring systems are reported: Hardman Index, Glasgow Aneurysm Score, Physiological and Operative Severity Score for Enumeration of Mortality and Morbidity (POSSUM), and the Vancouver Scoring System. No scoring system has been shown to have consistent or absolute validity. Of the remaining data, there are no individual or combination of variables that can accurately and consistently predict outcome.ConclusionsLittle robust evidence is available on which to base preoperative outcome prediction in patients with ruptured AAA. Experienced clinical judgement will remain of foremost importance in the selection of patients for ruptured AAA repair

An investigation of fuzzy multiple heuristic orderings in the construction of university examination timetables

In this paper, we present an investigation into using fuzzy methodologies to guide the construction of high quality feasible examination timetabling solutions. The provision of automated solutions to the examination timetabling problem is achieved through a combination of construction and improvement. The enhancement of solutions through the use of techniques such as metaheuristics is, in some cases, dependent on the quality of the solution obtained during the construction process. With a few notable exceptions, recent research has concentrated on the improvement of solutions as opposed to focusing on investigating the ‘best’ approaches to the construction phase. Addressing this issue, our approach is based on combining multiple criteria in deciding on how the construction phase should proceed. Fuzzy methods were used to combine three single construction heuristics into three different pair wise combinations of heuristics in order to guide the order in which exams were selected to be inserted into the timetable solution. In order to investigate the approach, we compared the performance of the various heuristic approaches with respect to a number of important criteria (overall cost penalty, number of skipped exams, number of iterations of a rescheduling procedure required and computational time) on 12 well-known benchmark problems.We demonstrate that the fuzzy combination of heuristics allows high quality solutions to be constructed. On one of the 12 problems, we obtained lower penalty than any previously published constructive method and for all 12 we obtained lower penalty than when any of the single heuristics were used alone. Furthermore, we demonstrate that the fuzzy approach used less backtracking when constructing solutions than any of the single heuristics. We conclude that this novel fuzzy approach is a highly effective method for heuristically constructing solutions and, as such, has particular relevance to real-world situations in which the construction of feasible solutions is often a difficult task in its own right