Optimal Uncertainty Quantification

We propose a rigorous framework for Uncertainty Quantification (UQ) in which the UQ objectives and the assumptions/information set are brought to the forefront. This framework, which we call \emph{Optimal Uncertainty Quantification} (OUQ), is based on the observation that, given a set of assumptions and information about the problem, there exist optimal bounds on uncertainties: these are obtained as values of well-defined optimization problems corresponding to extremizing probabilities of failure, or of deviations, subject to the constraints imposed by the scenarios compatible with the assumptions and information. In particular, this framework does not implicitly impose inappropriate assumptions, nor does it repudiate relevant information. Although OUQ optimization problems are extremely large, we show that under general conditions they have finite-dimensional reductions. As an application, we develop \emph{Optimal Concentration Inequalities} (OCI) of Hoeffding and McDiarmid type. Surprisingly, these results show that uncertainties in input parameters, which propagate to output uncertainties in the classical sensitivity analysis paradigm, may fail to do so if the transfer functions (or probability distributions) are imperfectly known. We show how, for hierarchical structures, this phenomenon may lead to the non-propagation of uncertainties or information across scales. In addition, a general algorithmic framework is developed for OUQ and is tested on the Caltech surrogate model for hypervelocity impact and on the seismic safety assessment of truss structures, suggesting the feasibility of the framework for important complex systems. The introduction of this paper provides both an overview of the paper and a self-contained mini-tutorial about basic concepts and issues of UQ.Comment: 90 pages. Accepted for publication in SIAM Review (Expository Research Papers). See SIAM Review for higher quality figure

Linking micro‐ and macroevolutionary perspectives to evaluate the role of Quaternary sea‐level oscillations in island diversification

With shifts in island area, isolation, and cycles of island fusion–fission, the role of Quaternary sea‐level oscillations as drivers of diversification is complex and not well understood. Here, we conduct parallel comparisons of population and species divergence between two island areas of equivalent size that have been affected differently by sea‐level oscillations, with the aim to understand the micro‐ and macroevolutionary dynamics associated with sea‐level change. Using genome‐wide datasets for a clade of seven Amphiacusta ground cricket species endemic to the Puerto Rico Bank (PRB), we found consistently deeper interspecific divergences and higher population differentiation across the unfragmented Western PRB, in comparison to the currently fragmented Eastern PRB that has experienced extreme changes in island area and connectivity during the Quaternary. We evaluate alternative hypotheses related to the microevolutionary processes (population splitting, extinction, and merging) that regulate the frequency of completed speciation across the PRB. Our results suggest that under certain combinations of archipelago characteristics and taxon traits, the repeated changes in island area and connectivity may create an opposite effect to the hypothesized “species pump” action of oscillating sea levels. Our study highlights how a microevolutionary perspective can complement current macroecological work on the Quaternary dynamics of island biodiversity.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141544/1/evo13384.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141544/2/evo13384_am.pd

Individual, unit and vocal clan level identity cues in sperm whale codas

Fieldwork was supported by Discovery and Equipment grants to H.W. from the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Whale and Dolphin Conservation Society. S.G. and L.R. were supported by the Marine Alliance for Science and Technology for Scotland (MASTs) pooling initiative and their support is gratefully acknowledged. MASTs is funded by the Scottish Funding Council (grant reference HR09011) and contributing institutions. S.G. was also supported by an NSERC Postgraduate Scholarship (PGS-M), an NSERC Canadian Graduate Scholarship (CGS-D), the Izaak Killam Memorial Scholarship, the Patrick F. Lett Fund, the Dalhousie’s Presidents Award, and an FNU fellowship for the Danish Council for Independent Research from the Ministry of Higher Education and Science supplemented by a Sapere Aude Research Talent Award.The ‘social complexity hypothesis’ suggests that complex social structure is a driver of diversity in animal communication systems. Sperm whales have a hierarchically structured society in which the largest affiliative structures, the vocal clans, are marked on ocean-basin scales by culturally transmitted dialects of acoustic signals known as ‘codas’. We examined variation in coda repertoires among both individual whales and social units—the basic element of sperm whale society—using data from nine Caribbean social units across six years. Codas were assigned to individuals using photo-identification and acoustic size measurement, and we calculated similarity between repertoires using both continuous and categorical methods. We identified 21 coda types. Two of those (‘1+1+3’ and ‘5R1’) made up 65% of the codas recorded, were shared across all units and have dominated repertoires in this population for at least 30 years. Individuals appear to differ in the way they produce ‘5R1’ but not ‘1+1+3’ coda. Units use distinct 4-click coda types which contribute to making unit repertoires distinctive. Our results support the social complexity hypothesis in a marine species as different patterns of variation between coda types suggest divergent functions, perhaps representing selection for identity signals at several levels of social structure.Publisher PDFPeer reviewe

RXJ0806.3+1527: a double degenerate binary with the shortest known orbital period (321s)

We carried out optical observations of the field of the X-ray pulsator RXJ0806.3+1527. A blue V=21.1 star was found to be the only object consistent with the X-ray position. VLT FORS spectra revealed a blue continuum with no intrinsic absorption lines. Broad (v~1500 km/s), low equivalent width (about -1/-6A) emission lines from the HeII Pickering series were clearly detected. B, V and R time-resolved photometry revealed the presence of about 15% pulsations at the 321s X-ray period, confirming the identification. These findings, together with the period stability and absence of any additional modulation in the 1min-5hr period range, argue in favour of the orbital interpretation of the 321s pulsations. The most likely scenario is thus that RXJ0806.3+1527 is a double degenerate system of the AM CVn class. This would make RXJ0806.3+1527 the shortest orbital period binary currently known and one of the best candidates for gravitational wave detection.Comment: Accepted for publication on A&A Letter

Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer

Both weekly cisplatin chemotherapy and single agent topotecan have proven to be effective in recurrent ovarian cancer. Preclinical data show synergism between cisplatin and topotecan. Side effects for this combination are drug sequence dependent and predominantly haematologic. Since preclinical data suggest that Cremophor EL (CrEL), the formulation vehicle of paclitaxel, has a protective effect on haematological toxicity of cisplatin, CrEL was added to the combination cisplatin and topotecan. In this phase I study, escalating doses of oral topotecan administered on day 1, 2, 8, 9, 15, 16, 29, 30, 36, 37, 43, 44 were combined with weekly cisplatin 70 mg m−2d−1on day 1, 8, 15, 29, 36, 43 (scheme A) or with the presumably less myelotoxic sequence weekly cisplatin day 2, 9, 16, 30, 37, 44 (scheme B). In scheme C, CrEL 12 ml was administered prior to cisplatin in the sequence of Scheme A. 18 patients have received a total of 85 courses. In scheme A 4/10 patients, all treated with topotecan 0.45 mg m−2d−1, experienced DLT: 1 patient had vomiting grade 4, 1 patient had grade 4 neutropenia >5 days, 1 patient had >2 weeks delay due to thrombocytopenia and 1 patient due to neutropenia. Both patients in scheme B (topotecan 0.45 mg m−2d−1) had DLT due to a delay > 2 weeks because of prolonged haematological toxicity. No DLT was observed in the first 3 patients in scheme C (topotecan 0.45 mg m−2d−1). However, 2 out of 3 patients treated at dose level topotecan 0.60 mg m−2d−1in scheme C experienced DLT due to >2 weeks delay because of persistent thrombocytopenia or neutropenia. We conclude that there is a modest clinical effect of CrEL on haematological toxicity for this cisplatin-based combination regimen, which seems to reduce these side effects but does not really enable an increase of the oral topotecan dose. © 2001 Cancer Research Campaign  http://www.bjcancer.co

Clinical use of HIV integrase inhibitors : a systematic review and meta-analysis

Background: Optimal regimen choice of antiretroviral therapy is essential to achieve long-term clinical success. Integrase inhibitors have swiftly been adopted as part of current antiretroviral regimens. The purpose of this study was to review the evidence for integrase inhibitor use in clinical settings. Methods: MEDLINE and Web-of-Science were screened from April 2006 until November 2012, as were hand-searched scientific meeting proceedings. Multiple reviewers independently screened 1323 citations in duplicate to identify randomized controlled trials, nonrandomized controlled trials and cohort studies on integrase inhibitor use in clinical practice. Independent, duplicate data extraction and quality assessment were conducted. Results: 48 unique studies were included on the use of integrase inhibitors in antiretroviral therapy-naive patients and treatment-experienced patients with either virological failure or switching to integrase inhibitors while virologically suppressed. On the selected studies with comparable outcome measures and indication (n = 16), a meta-analysis was performed based on modified intention-to-treat (mITT), on-treatment (OT) and as-treated (AT) virological outcome data. In therapy-naive patients, favorable odds ratios (OR) for integrase inhibitor-based regimens were observed, (mITT OR 0.71, 95% CI 0.59-0.86). However, integrase inhibitors combined with protease inhibitors only did not result in a significant better virological outcome. Evidence further supported integrase inhibitor use following virological failure (mITT OR 0.27; 95% CI 0.11-0.66), but switching to integrase inhibitors from a high genetic barrier drug during successful treatment was not supported (mITT OR 1.43; 95% CI 0.89-2.31). Integrase inhibitor-based regimens result in similar immunological responses compared to other regimens. A low genetic barrier to drug-resistance development was observed for raltegravir and elvitegravir, but not for dolutegravir. Conclusion: In first-line therapy, integrase inhibitors are superior to other regimens. Integrase inhibitor use after virological failure is supported as well by the meta-analysis. Careful use is however warranted when replacing a high genetic barrier drug in treatment-experienced patients switching successful treatment

Generation of a wave packet tailored to efficient free space excitation of a single atom

We demonstrate the generation of an optical dipole wave suitable for the process of efficiently coupling single quanta of light and matter in free space. We employ a parabolic mirror for the conversion of a transverse beam mode to a focused dipole wave and show the required spatial and temporal shaping of the mode incident onto the mirror. The results include a proof of principle correction of the parabolic mirror's aberrations. For the application of exciting an atom with a single photon pulse we demonstrate the creation of a suitable temporal pulse envelope. We infer coupling strengths of 89% and success probabilities of up to 87% for the application of exciting a single atom for the current experimental parameters.Comment: to be published in Europ. Phys. J.

Renal function of MDR-TB patients treated with kanamycin regimens or concomitantly with antiretroviral agents

SETTING: To compare renal insufficiency among mul-tidrug-resistant tuberculosis (MDR-TB) patients treated with kanamycin (KM) based regimens and those treated concomitantly with tenofovir disoproxil fumarate (TDF) or other antiretroviral therapy (ART) regimens in Namibia. DESIGN: Retrospective review of the treatment records and laboratory tests of patients initiated on MDR-TB treatment (January–December 2014). The glomerular filtration rates (eGFR) estimated pre- and post-treatment were compared using the analysis of variance test. Renal insufficiency was defined as an eGFR of,60 ml/ min/1.73 m2. Use of KM or TDF and association with renal insufficiency was assessed using Kaplan-Meier plots and Cox proportional hazards analysis. RESULTS: The baseline mean eGFR for the three groups was similar (P ¼ 0.24): 139.3 6 25.6 ml/min for the KM group (n ¼ 68), 131.1 6 25.7 ml/min for the KMþTDF group (n ¼ 44) and 134.2634.4 ml/min for the KMþOther group (n ¼ 23). After 8 months, the values had declined significantly to respectively 104.8 6 37.5 ml/min (P, 0.001), 101.5 6 38.3 ml/min (P, 0.001) and 111.5 6 41.7 ml/min (P ¼ 0.01). Co-treatment with KMþART was associated with an increased risk of renal insufficiency (hazard ratio [HR] 1.8, 95%CI 0.7–4.1, P ¼ 0.20 for KMþTDF, and HR 3.5, 95%CI 1.4–8.2, P ¼ 0.005 for KMþOther ART). CONCLUSION: Renal function declined at a similar rate in MDR-TB patients treated with KM-based regimens compared with patients treated concomitantly with TDF-based or other ART. The risk of renal insufficiency was greater for patients on ART

Non-adherence to guideline recommendations for insulins:: a qualitative study amongst primary care practitioners

Background: Guideline adherence is generally high in Dutch general practices. However, the prescription of insulins to type 2 diabetes mellitus patients is often not in line with the guideline, which recommends NPH insulin as first choice and discourages newer insulins. This qualitative study aimed to identify the reasons why primary care healthcare professionals prescribe insulins that are not recommended in guidelines. Methods: Digital focus groups with primary care practitioners were organised. A topic list was developed, based on reasons for preferred insulins obtained from literature and a priori expert discussions. The discussions were video and audio-recorded, transcribed verbatim and coded with a combination of inductive and deductive codes. Codes were categorized into an existing knowledge, attitudes and behaviour model for guideline non-adherence. Results: Four focus groups with eleven general practitioners, twelve practice nurses, six pharmacists, four diabetes nurses and two nurse practitioners were organised. The prescription of non-recommended insulins was largely driven by argumentation in the domain of attitudes. Lack of agreement with the guideline was the most prominent category. Most of those perspectives did not reflect disagreement with the guideline recommendations in general, but were about advantages of non-recommended insulins, which led, according to the healthcare professionals, to better applicability of those insulins to specific patients. The belief that guideline-recommended insulins were less effective, positive experience with other insulins and marketing from pharmaceutical companies were also identified as attitude-related barriers to prescribe guideline-recommended insulins. One additional category in the domain of attitudes was identified, namely the lack of uniformity in policy between healthcare professionals in the same practice. Only a small number of external barriers were identified, focusing on patient characteristics that prevented the use of recommended insulins, the availability of contradictory guidelines and other, mostly secondary care, healthcare providers initiating non-recommended insulins. No knowledge-related barriers were identified. Conclusions: The prescription of non-recommended insulins in primary care is mostly driven by lack of agreement with the guideline recommendations and different interpretation of evidence. These insights can be used for the development of interventions to stimulate primary care practitioners to prescribe guideline-recommended insulins