'Some tactical problems in digital simulation' for the next 10 years

In his influential 1963 paper ‘Some Tactical Problems in Digital Simulation’, Conway identified important issues that became the pillars of research in simulation analysis methodology. Naturally these ‘problems’ were a product of the applications of interest at the time, as well as the state of simulation and computing, much of which has changed dramatically. In light of those changes, we attempt to identify the tactical problems that might occupy simulation researchers for the next 10 years

Input uncertainty quantification for simulation models with piecewise-constant non-stationary Poisson arrival processes

Input uncertainty (IU) is the outcome of driving simulation models using input distributions estimated by finite amounts of real-world data. Methods have been presented for quantifying IU when stationary input distributions are used. In this paper we extend upon this work and provide two methods for quantifying IU in simulation models driven by piecewise-constant non-stationary Poisson arrival processes. Numerical evaluation and illustrations of the methods are provided and indicate that the methods perform well

Mass fluxes and isofluxes of methane (CH4) at a New Hampshire fen measured by a continuous wave quantum cascade laser spectrometer

We have developed a mid‐infrared continuous‐wave quantum cascade laser direct‐absorption spectrometer (QCLS) capable of high frequency (≥1 Hz) measurements of 12CH4 and 13CH4 isotopologues of methane (CH4) with in situ 1‐s RMS image precision of 1.5 ‰ and Allan‐minimum precision of 0.2 ‰. We deployed this QCLS in a well‐studied New Hampshire fen to compare measurements of CH4 isoflux by eddy covariance (EC) to Keeling regressions of data from automated flux chamber sampling. Mean CH4 fluxes of 6.5 ± 0.7 mg CH4 m−2 hr−1 over two days of EC sampling in July, 2009 were indistinguishable from mean autochamber CH4 fluxes (6.6 ± 0.8 mgCH4 m−2 hr−1) over the same period. Mean image composition of emitted CH4 calculated using EC isoflux methods was −71 ± 8 ‰ (95% C.I.) while Keeling regressions of 332 chamber closing events over 8 days yielded a corresponding value of −64.5 ± 0.8 ‰. Ebullitive fluxes, representing ∼10% of total CH4 fluxes at this site, were on average 1.2 ‰ enriched in 13C compared to diffusive fluxes. CH4 isoflux time series have the potential to improve process‐based understanding of methanogenesis, fully characterize source isotopic distributions, and serve as additional constraints for both regional and global CH4 modeling analysis

Detecting bias due to input modelling in computer simulation

Bias due to input modelling is almost always assumed negligible and ignored. It is known that increasing the amount of real-world data available for modelling input processes causes this form of bias to decrease faster than the variance due to input uncertainty. However, this does not mean bias is irrelevant when considering the error in a simulation performance measure caused by input modelling. In this paper we present a response surface approach to bias estimation in simulation models along with a diagnostic test for identifying, with controlled power, bias due to input modelling of a size that would be concerning to a practitioner

Improving the efficiency of genomic loci capture using oligonucleotide arrays for high throughput resequencing

<p>Abstract</p> <p>Background</p> <p>The emergence of next-generation sequencing technology presents tremendous opportunities to accelerate the discovery of rare variants or mutations that underlie human genetic disorders. Although the complete sequencing of the affected individuals' genomes would be the most powerful approach to finding such variants, the cost of such efforts make it impractical for routine use in disease gene research. In cases where candidate genes or loci can be defined by linkage, association, or phenotypic studies, the practical sequencing target can be made much smaller than the whole genome, and it becomes critical to have capture methods that can be used to purify the desired portion of the genome for shotgun short-read sequencing without biasing allelic representation or coverage. One major approach is array-based capture which relies on the ability to create a custom in-situ synthesized oligonucleotide microarray for use as a collection of hybridization capture probes. This approach is being used by our group and others routinely and we are continuing to improve its performance.</p> <p>Results</p> <p>Here, we provide a complete protocol optimized for large aggregate sequence intervals and demonstrate its utility with the capture of all predicted amino acid coding sequence from 3,038 human genes using 241,700 60-mer oligonucleotides. Further, we demonstrate two techniques by which the efficiency of the capture can be increased: by introducing a step to block cross hybridization mediated by common adapter sequences used in sequencing library construction, and by repeating the hybridization capture step. These improvements can boost the targeting efficiency to the point where over 85% of the mapped sequence reads fall within 100 bases of the targeted regions.</p> <p>Conclusions</p> <p>The complete protocol introduced in this paper enables researchers to perform practical capture experiments, and includes two novel methods for increasing the targeting efficiency. Coupled with the new massively parallel sequencing technologies, this provides a powerful approach to identifying disease-causing genetic variants that can be localized within the genome by traditional methods.</p

Simultaneous Measurements of Atmospheric HONO and NO2 via Absorption Spectroscopy using Tunable Mid-Infrared Continuous-wave Quantum Cascade Lasers

Nitrous acid (HONO) is important as a significant source of hydroxyl radical (OH) in the troposphere and as a potent indoor air pollutant. It is thought to be generated in both environments via heterogeneous reactions involving nitrogen dioxide $(NO_2)$. In order to enable fast-response HONO detection suitable for eddy-covariance flux measurements and to provide a direct method that avoids interferences associated with derivatization, we have developed a 2-channel tunable infrared laser differential absorption spectrometer (TILDAS) capable of simultaneous high-frequency measurements of HONO and NO2. Beams from two mid-infrared continuous-wave mode quantum cascade lasers (cw-QCLs) traverse separate 210 m paths through a multi-pass astigmatic sampling cell at reduced pressure for the direct detection of HONO $(1660 cm^{−1})$ and $(NO_2)$ $(1604 cm^{−1})$. The resulting one-second detection limits (S/N=3) are 300 and 30 ppt (pmol/mol) for HONO and $(NO_2)$, respectively. Our HONO quantification is based on revised line-strengths and peak positions for cis-HONO in the 6-micron spectral region that were derived from laboratory measurements. An essential component of ambient HONO measurements is the inlet system and we demonstrate that heated surfaces and reduced pressure minimize sampling artifacts.Earth and Planetary SciencesEngineering and Applied Science

Airline Disruption Recovery Using Symbiotic Simulation and Multi-fidelity Modelling

The airlines industry is prone to disruption due to various causes. Whilst an airline may not be able to control the causes of disruption, it can reduce the impact of a disruptive event, such as a mechanical failure, with its response by revising the schedule. Potential actions include swapping aircraft, delaying flights and cancellations. This paper will present our research into how symbiotic simulation could potentially be used to improve the response to a disruptive event by evaluating potential revised schedules. Due to the large solution space, exhaustive searches are infeasible. Our research is investigating the use of multi-fidelity models to help guide the search of the optimisation algorithm, leading to good solutions being generated within the time constraints of disruption management

U87MG Decoded: The Genomic Sequence of a Cytogenetically Aberrant Human Cancer Cell Line

U87MG is a commonly studied grade IV glioma cell line that has been analyzed in at least 1,700 publications over four decades. In order to comprehensively characterize the genome of this cell line and to serve as a model of broad cancer genome sequencing, we have generated greater than 30× genomic sequence coverage using a novel 50-base mate paired strategy with a 1.4kb mean insert library. A total of 1,014,984,286 mate-end and 120,691,623 single-end two-base encoded reads were generated from five slides. All data were aligned using a custom designed tool called BFAST, allowing optimal color space read alignment and accurate identification of DNA variants. The aligned sequence reads and mate-pair information identified 35 interchromosomal translocation events, 1,315 structural variations (>100 bp), 191,743 small (<21 bp) insertions and deletions (indels), and 2,384,470 single nucleotide variations (SNVs). Among these observations, the known homozygous mutation in PTEN was robustly identified, and genes involved in cell adhesion were overrepresented in the mutated gene list. Data were compared to 219,187 heterozygous single nucleotide polymorphisms assayed by Illumina 1M Duo genotyping array to assess accuracy: 93.83% of all SNPs were reliably detected at filtering thresholds that yield greater than 99.99% sequence accuracy. Protein coding sequences were disrupted predominantly in this cancer cell line due to small indels, large deletions, and translocations. In total, 512 genes were homozygously mutated, including 154 by SNVs, 178 by small indels, 145 by large microdeletions, and 35 by interchromosomal translocations to reveal a highly mutated cell line genome. Of the small homozygously mutated variants, 8 SNVs and 99 indels were novel events not present in dbSNP. These data demonstrate that routine generation of broad cancer genome sequence is possible outside of genome centers. The sequence analysis of U87MG provides an unparalleled level of mutational resolution compared to any cell line to date

Governance, ownership structure and performance of IPO firms: the impact of different types of private equity investors and institutional environments

This paper examines performance effects of ownership concentration and two types of private equity investors (venture capitalists and business angels) in firms that have recently undergone an initial public offering (IPO) in the United Kingdom and France. We expand and contextualize nascent understanding of multiple agency theory by examining heterogeneity of private equity investors and by suggesting that multiple agency relationships are affected by different institutional contexts. We employ a unique, hand-collected dataset of 224 matched IPOs (112 in each country). Controlling for the endogeneity of private equity investors’ retained share ownership, we find support for the agency theory argument that concentrated ownership improves IPO’s performance. The research also shows that the two types of private equity investors have a differential impact on performance, and the legal institutions in a given country moderate this impact