847 research outputs found
Efficient Computation of Probabilities of Events Described by Order Statistics and Applications to Queue Inference
This paper derives recursive algorithms for efficiently computing event probabilities related to order statistics and applies the results in a queue inferencing setting. Consider a set of N i.i.d. random variables in [0, 1]. When the experimental values of the random variables are arranged in ascending order from smallest to largest, one has the order statistics of the set of random variables. Both a forward and a backward recursive O(N3 ) algorithm are developed for computing the probability that the order statistics vector lies in a given N-rectangle. The new algorithms have applicability in inferring the statistical behavior of Poisson arrival queues, given only the start and stop times of service of all N customers served in a period of continuous congestion. The queue inference results extend the theory of the "Queue Inference Engine" (QIE), originally developed by Larson in 1990 [8]. The methodology is extended to a third O(N 3 ) algorithm, employing both forward and backward recursion, that computes the conditional probability that a random customer of the N served waited in queue less than r minutes, given the observed customer departure times and assuming first come, first served service. To our knowledge, this result is the first O(N3 ) exact algorithm for computing points on the in-queue waiting time distribution function,conditioned on the start and stop time data. The paper concludes with an extension to the computation of certain correlations of in-queue waiting times. Illustrative computational results are included throughout
Efficient Computation of Probabilities of Events Described by Order Statistics and Application to a Problem of Queues
Consider a set of N i.i.d. random variables in [0, 1]. When the experimental values of the random variables are arranged in ascending order from smallest to largest, one has the order statistics of the set of random variables. In this note an O(N3) algorithm is developed for computing the probability that the order statistics vector lies in a given rectangle. The new algorithm is then applied to a problem of statistical inference in queues. Illustrative computational results are included
Laboratory Focus on Improving the Culture of Biosafety: Statewide Risk Assessment of Clinical Laboratories That Process Specimens for Microbiologic Analysis
The Wisconsin State Laboratory of Hygiene challenged Wisconsin laboratories to examine their biosafety practices and improve their culture of biosafety. One hundred three clinical and public health laboratories completed a questionnaire-based, microbiology-focused biosafety risk assessment. Greater than 96% of the respondents performed activities related to specimen processing, direct microscopic examination, and rapid nonmolecular testing, while approximately 60% performed culture interpretation. Although they are important to the assessment of risk, data specific to patient occupation, symptoms, and travel history were often unavailable to the laboratory and, therefore, less contributory to a microbiology-focused biosafety risk assessment than information on the specimen source and test requisition. Over 88% of the respondents complied with more than three-quarters of the mitigation control measures listed in the survey. Facility assessment revealed that subsets of laboratories that claim biosafety level 1, 2, or 3 status did not possess all of the biosafety elements considered minimally standard for their respective classifications. Many laboratories reported being able to quickly correct the minor deficiencies identified. Task assessment identified deficiencies that trended higher within the general (not microbiology-specific) laboratory for core activities, such as packaging and shipping, direct microscopic examination, and culture modalities solely involving screens for organism growth. For traditional microbiology departments, opportunities for improvement in the cultivation and management of highly infectious agents, such as acid-fast bacilli and systemic fungi, were revealed. These results derived from a survey of a large cohort of small- and large-scale laboratories suggest the necessity for continued microbiology-based understanding of biosafety practices, vigilance toward biosafety, and enforcement of biosafety practices throughout the laboratory setting
The Role of Column Density in the Formation of Stars and Black Holes
The stellar mass in disk galaxies scales approximately with the fourth power
of the rotation velocity, and the masses of the central black holes in galactic
nuclei scale approximately with the fourth power of the bulge velocity
dispersion. It is shown here that these relations can be accounted for if, in a
forming galaxy with an isothermal mass distribution, gas with a column density
above about 8 Msun/pc^2 goes into stars while gas with a column density above
about 2 g/cm^2 (10^4 Msun/pc^2) goes into a central black hole. The lower
critical value is close to the column density of about 10 Msun/pc^2 at which
atomic gas becomes molecular, and the upper value agrees approximately with the
column density of about 1 g/cm^2 at which the gas becomes optically thick to
its cooling radiation. These results are plausible because molecule formation
is evidently necessary for star formation, and because the onset of a high
optical depth in a galactic nucleus may suppress continuing star formation and
favour the growth of a central black hole.Comment: Accepted by Nature Physic
Outliers from the Mass--Metallicity Relation II: A Sample of Massive Metal-Poor Galaxies from SDSS
We present a sample of 42 high-mass low-metallicity outliers from the
mass--metallicity relation of star-forming galaxies. These galaxies have
stellar masses that span log(M_*/M_sun) ~9.4 to 11.1 and are offset from the
mass--metallicity relation by -0.3 to -0.85 dex in 12+log(O/H). In general,
they are extremely blue, have high star formation rates for their masses, and
are morphologically disturbed. Tidal interactions are expected to induce
large-scale gas inflow to the galaxies' central regions, and we find that these
galaxies' gas-phase oxygen abundances are consistent with large quantities of
low-metallicity gas from large galactocentric radii diluting the central
metal-rich gas. We conclude with implications for deducing gas-phase
metallicities of individual galaxies based solely on their luminosities,
specifically in the case of long gamma-ray burst host galaxies.Comment: Accepted for publication in ApJ; 11 pages, 11 figure
Angular Momentum and the Formation of Stars and Black Holes
The formation of compact objects like stars and black holes is strongly
constrained by the requirement that nearly all of the initial angular momentum
of the diffuse material from which they form must be removed or redistributed
during the formation process. The mechanisms that may be involved and their
implications are discussed for (1) low-mass stars, most of which probably form
in binary or multiple systems; (2) massive stars, which typically form in
clusters; and (3) supermassive black holes that form in galactic nuclei. It is
suggested that in all cases, gravitational interactions with other stars or
mass concentrations in a forming system play an important role in
redistributing angular momentum and thereby enabling the formation of a compact
object. If this is true, the formation of stars and black holes must be a more
complex, dynamic, and chaotic process than in standard models. The
gravitational interactions that redistribute angular momentum tend to couple
the mass of a forming object to the mass of the system, and this may have
important implications for mass ratios in binaries, the upper stellar IMF in
clusters, and the masses of supermassive black holes in galaxies.Comment: Accepted by Reports on Progress in Physic
VarScan 2: Somatic mutation and copy number alteration discovery in cancer by exome sequencing
Cancer is a disease driven by genetic variation and mutation. Exome sequencing can be utilized for discovering these variants and mutations across hundreds of tumors. Here we present an analysis tool, VarScan 2, for the detection of somatic mutations and copy number alterations (CNAs) in exome data from tumor–normal pairs. Unlike most current approaches, our algorithm reads data from both samples simultaneously; a heuristic and statistical algorithm detects sequence variants and classifies them by somatic status (germline, somatic, or LOH); while a comparison of normalized read depth delineates relative copy number changes. We apply these methods to the analysis of exome sequence data from 151 high-grade ovarian tumors characterized as part of the Cancer Genome Atlas (TCGA). We validated some 7790 somatic coding mutations, achieving 93% sensitivity and 85% precision for single nucleotide variant (SNV) detection. Exome-based CNA analysis identified 29 large-scale alterations and 619 focal events per tumor on average. As in our previous analysis of these data, we observed frequent amplification of oncogenes (e.g., CCNE1, MYC) and deletion of tumor suppressors (NF1, PTEN, and CDKN2A). We searched for additional recurrent focal CNAs using the correlation matrix diagonal segmentation (CMDS) algorithm, which identified 424 significant events affecting 582 genes. Taken together, our results demonstrate the robust performance of VarScan 2 for somatic mutation and CNA detection and shed new light on the landscape of genetic alterations in ovarian cancer
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Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.
BackgroundInternal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia.MethodsIn this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing.FindingsBetween Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials.FundingAstellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro
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