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Standard approaches to stochastic gradient estimation, with only noisy black-box function evaluations, use the finite-difference method or its variants. Though natural, it is open to our knowledge whether their statistical accuracy is the best possible. This paper argues so by showing that central finite-difference is a nearly minimax optimal zeroth-order gradient estimator for a suitable class of objective functions and mean squared risk, among both the class of linear estimators and the much larger class of all (nonlinear) estimators.

Radiation dermatitis is a common adverse effect of radiotherapy (RT) in breast cancer patients. Although radiation dermatitis is reported by either the clinician or the patient, previous studies have shown disagreement between clinician-reported outcomes (CROs) and patient-reported outcomes (PROs). This review evaluated the extent of discordance between CROs and PROs for radiation dermatitis. Studies reporting both clinician and patient-reported outcomes for external beam RT were eligible. Nine studies met the inclusion criteria for the systematic review, while 8 of these studies were eligible for inclusion in a meta-analysis of acute and late skin toxicities. We found an overall agreement between CROs and PROs of acute skin colour change, fibrosis and/or retraction, and moist desquamation (p > 0.005). Reporting of late breast pain, breast edema, skin colour change, telangiectasia, fibrosis and/or retraction and induration/fibrosis alone (p > 0.005) were also in agreement between clinicians and patients. Our meta-analysis revealed a greater reporting of acute breast pain by patients (RR = 0.89, 95% CI 0.87–0.92, p, Highlights • Patient- and clinician-reported outcomes generally demonstrated high levels of agreement. • Patients reported more acute breast pain and late breast shrinkage than clinicians. • Clinicians reported more acute breast edema than patients. • The measurement tools and time points at which radiotherapy side effects were assessed varied considerably across studies. • Standardized reporting of radiotherapy side effects by clinicians and patients could impact future symptom management.

Insufficient chromatographic performance results in reduced utilization of MS/MS scan capacity of advanced MS instruments. Improvement in peptide separation in liquid chromatography is critical for increasing the sensitivity and quantification performance of LC-MS-based proteomics. However, existing column fabrication methods suffer from slow packing, large dead volume, and band broadening. Herein, we reported that directly pulling emitter tips within short frits after fast packing (termed "filled tip") can minimize the dead volume, improving ionization efficiency and reducing band broadening. Within 10 min, our method can pack over 10 cm for 50 μm I.D. capillary columns under 6-8 MPa and over 50 cm for 75 μm I.D. long capillary columns under 70 MPa. We can identify an average of 3043 protein groups and 33 309 peptide-spectrum matches (PSMs) from 1 ng of HeLa digest using a 50 μm I.D. x 20 cm "filled tip" column, with good reproducibility. The number of protein groups increased by 50% and 96% when compared with a 50 μm I.D. "void tip" column and a 100 μm I.D. column with a manually pulled tip, respectively. We identified an average of 5534 protein groups and 71 769 PSMs from 10 ng of HeLa digest. In addition, using 75 μm I.D. x 50 cm "filled tip" columns, we can identify on average 8829 protein groups and 170 751 PSMs in single-shot data-dependent acquisition analysis from 500 ng of 293T digested peptides. Importantly, good repeatability and reproducibility of "filled tip" method were verified by results from columns fabricated in three batches and by different persons. When compared with conventional columns with "void tips", "filled tip" columns reduced median full peak widths by 19% and alleviated sampling redundancy by 10%. Collectively, we developed an easy-to-use, versatile and robust column fabrication method for both narrow-bore and long capillary columns, which achieved great sensitivity and depth in proteomic analysis.

Assortment optimization is an important problem in revenue management arising in industries such as online advertising, retailing and airline ticketing. We study assortment optimization under an arbitrary mixture of multi-nomial logit (MNL) models, when the universe of products is dense. In general, it is NP-hard to approximate assortment optimization under mixture of MNLs model within any reasonable factor. However, if the universe of products is dense, we show that assortment optimization has an optimal solution that is well approximated by a nested-by-revenue policy. We argue this by considering an alternate, continuous-space model where product features follow a density on a continuous space, and offer set can be any open subset on the feature space. In this model, we show that there exists a nested-by-revenue policy that is optimal. This characterization holds regardless of the mixture distribution (including discrete and continuous) and the dimension of feature space. Through this characterization and linking the continuous-space to the standard discrete-item model via a "fractional" relaxation, we also show that, in the finite and discrete item case, nested-by-revenue performs nearly optimally. In particular, we derive an optimality gap, explicitly dependent on the model parameters, that shrinks to zero under suitable scaling as the number of items grows.

We study a methodology to tackle the NASA Langley Uncertainty Quantification Challenge, a model calibration problem under both aleatory and epistemic uncertainties. Our methodology is based on an integration of robust optimization, more specifically a recent line of research known as distributionally robust optimization, and importance sampling in Monte Carlo simulation. The main computation machinery in this integrated methodology amounts to solving sampled linear programs. We present theoretical statistical guarantees of our approach via connections to nonparametric hypothesis testing, and numerical performances including parameter calibration and downstream decision and risk evaluation tasks., Comment: arXiv admin note: substantial text overlap with arXiv:2006.15689

Despite the prevalence of radiation dermatitis in breast cancer patients, current practice guidelines for its treatment are limited. We aimed to discuss the quality of evidence for the barrier-forming Mepitel Film for prophylaxis of radiation dermatitis, and argue for further investigation into evidence-based management of skin toxicities. Two studies assessing Mepitel Film were critically evaluated. Both reported that Mepitel Film decreased radiation dermatitis; moreover, patient-reported outcomes significantly favoured Mepitel Film. However, there has not been global adoption of barrier-forming films such as Mepitel, in part due to the absence of multi-centred randomised trials and the heterogeneity of study designs.

Background and purpose Impending or pathological fractures due to bone metastases may require surgical fixation. Postoperative radiation is often recommended to reduce local progression and prevent prosthesis displacement, hence reducing the need for second surgery. The objectives of this study were to investigate the need for second surgery, and to report on rates of re-irradiation, tumor progression and prosthesis displacement following postoperative radiation. Materials and methods Data were collected from 65 patients who received postoperative radiation to 74 sites in the extremities in a palliative radiation clinic between January 2009 and January 2017. Descriptive statistical analyses were performed. Results Only 2 patients required a second surgery (2.7%) at 9 and 10months after postoperative radiation. Increase in pain requiring re-irradiation was reported in 7 patients (9.5%), at a median time of 9.3months after the delivery of radiation. Of the 47 patients who had radiological imaging available post-radiation, local progression of bone metastases was seen in 8 patients (17.0%) and displacement of the prosthesis in 1 patient (2.1%). Conclusion Rates of prosthesis displacement and progression of bone metastases at site of surgery were low after postoperative radiation. There were few incidences of second surgery and re-irradiation observed in the cohort. These findings provide support for the benefit of postoperative radiation.

We study the empirical likelihood approach to construct confidence intervals for the optimal value and the optimality gap of a given solution, henceforth quantify the statistical uncertainty of sample average approximation, for optimization problems with expected value objectives and constraints where the underlying probability distributions are observed via limited data. This approach relies on two distributionally robust optimization problems posited over the uncertain distribution, with a divergence-based uncertainty set that is suitably calibrated to provide asymptotic statistical guarantees.

Background: Radiation therapy is effective for painful uncomplicated bone metastases, with multiple fraction radiation therapy (MFRT) administered frequently. The optimal dose for MFRT to yield maximum pain relief remains unclear. The aim of this systematic review was to determine pain response across MFRT doses. Methods: A literature search was conducted in Ovid MEDLINE(R) , Embase Classic & Embase and Cochrane Central Register of Controlled Trials . Pain response rates and the side effects for MFRT doses were extracted. Results: From the 3719 articles identified from the search, 17 were included for quantitative synthesis. 22.5Gy/5 had the highest overall response (OR) rate, 30Gy/15 had better complete response (CR) rate and 20Gy/2 had better partial response (PR) rate. Only 4 of the 17 included studies directly compared MFRT doses with each other – one reported marginally-better OR for 24Gy/6 over 20Gy/2; another found 20Gy/10 to be slightly more efficacious than 30Gy/15 and 22.5Gy/5 for OR. Two randomized trials compared 20Gy/5 and 30Gy/10 – one favored 20Gy/5 while the other concluded 30Gy/10 to be the better option. The overall rate of GI toxicities, nausea, and vomiting did not differ greatly between MFRT doses. Conclusion: No major difference exists between the schedules and toxic events studied in these trials. This is consistent with the wealth of randomized data which show no dose response for pain relief after radiotherapy for metastatic bone pain.

Despite the documented benefits of ride-sourcing services, recent studies show that they can slow down traffic in the densest cities significantly. To implement congestion pricing policies upon those vehicles, regulators need to estimate how much their congestion effects are. This paper studies simulation-based approaches to address the two technical challenges arising from the representation of system dynamics and the optimization for congestion price mechanisms. To estimate the traffic conditions, we use a meta-model representation for traffic flow and a numerical method for data interpolation. To reduce the burden of replicating evaluation in stochastic optimization, we use a simulation optimization approach to compute the optimal congestion price. This data-driven approach can potentially be extended to solve large-scale congestion pricing problems with unobservable states.

Introduction Heterotopic ossification (HO) involves the formation of lamellar bone in nonosseous tissue. For HO, radiotherapy has been shown to be an effective prophylactic modality. Objective To compare HO outcomes following radiotherapy and to investigate the comparative efficacy of preoperative versus postoperative radiotherapy. Methods A systematic search was conducted on Ovid MEDLINE, EMBASE and Cochrane CENTRAL. Studies were included if they were randomized controlled trials (RCTs) that included patients who were prescribed prophylactic radiation for whom relevant HO progression outcomes were reported. Results From a literature search of 528 articles, 12 RCTs were included. There was a statistically significant reduction in HO prevalence with multiple as opposed to single fraction radiotherapy ( p =0.04), however there was no statistically significant difference when examining HO progression ( p =0.34). There was no statistically significant difference in HO progression when comparing a biologically effective radiation dose (BED) of >2500cGy versus ⩽2500cGy ( p =0.28). As well, no statistically significant difference existed in HO progression between postoperative versus preoperative radiation ( p =0.43). Conclusion There was no difference between postoperative or preoperative radiotherapy in preventing HO progression. There seems to be no relationship between BED greater or less than 2500cGy and the efficacy of HO prophylaxis. Multiple fractions seem to be more effective than single fraction radiotherapy in preventing HO progression.

The goal of this research is to investigate how classroom second language learners of German living in Western Canada perceive language variation in terms of dialects of German. A three-part linguistic experiment was carried out over the course of one semester with twenty university students of German, most of whom were native speakers of English. The first task required participants to discriminate dialects from the standard language. Secondly, they completed an intelligibility task to demonstrate their understanding of dialects. In the final task participants indicated their attitudes towards dialects. We found that the discrimination ability of participants was generally high, and that language proficiency predicted their ability to discriminate. That is, the most proficient learners were best able to determine whether speech samples are spoken in dialect or in standard German. Intelligibility (i.e., the ability to understand what was being said) was generally poor and was unaffected by language proficiency. Participants found certain dialects to be more pleasant than others. The results of the study point to the importance of exposing students to—and valuing the legitimacy of—non-standard language varieties.

Introduction Following surgery, the formation of heterotopic ossification (HTO) can limit mobility and impair quality of life. Radiotherapy has been proven to provide efficacious prophylaxis against HTO, especially in high-risk settings. Purpose The current review aims to determine the factors influencing HTO formation in patients receiving prophylactic radiotherapy. Methods A systematic search of the literature was conducted on Ovid Medline, Embase and the Cochrane Central Register of Controlled Trials. Studies were included if they reported the percentage of sites developing heterotopic ossification after receiving a specified dose of prophylactic radiotherapy. Weighted linear regression analysis was conducted for continuous or categorical predictors. Results Extracted from 61 articles, a total of 5464 treatment sites were included, spanning 85 separate study arms. Most sites were from the hip (97.7%), from United States patients (55.2%), and had radiation prescribed postoperatively (61.6%) at a dose of 700cGy (61.0%). After adjusting for radiation site, there was no statistically significant relationship between the percentage of sites developing HTO and radiation dose ( p =0.1) or whether radiation was administered preoperatively or postoperatively ( p =0.1). Sites with previous HTO formation were more likely to develop recurrent HTO than those without previous HTO formation ( p =0.04). There was a statistically significant negative relationship between the HTO development and the cohort mean year of treatment ( p =0.007). Conclusion Decreases in rates of HTO over time in this patient population may be a function of more efficacious surgical regimens and prophylactic radiotherapy.

Background and purpose Numerous randomized controlled trials and meta-analyses have affirmed that single and multiple fractions of radiotherapy provide equally efficacious outcomes in the palliation of painful, uncomplicated bone metastases (UBM). We aim to determine geographic, temporal and ancillary factors that influence the global patterns of practice in this setting. Materials and methods A literature search was conducted on Ovid MEDLINE and EMBASE. Studies were included if they disclosed prescription patterns of single fraction radiotherapy, either through hypothetical cases or actual patient data. Weighted analysis of variance was conducted for binary predictors while weighted linear regression analysis was performed for continuous parameters. Results Nine hypothetical case studies and thirteen actual patterns of practice articles were included from 301 search results. Radiation oncologists prescribed dose fractionations ranging from 3 Gy × 1 to 2 Gy × 30, with a median of 3 Gy × 10, for the palliation of UBM. Actual data demonstrated a weak, non-significant, negative linear relationship between the use of single fraction radiotherapy and the year of treatment. Geographical location of treatment was a key predictor of prescription patterns. Conclusion In the last twenty years, there was an overall global reluctance to practice evidence-based medicine by employing single fractions for UBM.

We explore a new framework to approximate life insurance risk processes in the scenario of plentiful policyholders, via a bottom-up approach. Given the insurance contract structure, we aggregate the balance of individual policy accounts, and derive an approximating Gaussian process with computable correlation structure. The methodology is borrowed from heavy traffic theory in the literature of many-server queues, and involves the so-called fluid and diffusion approximations. Our framework is different from the individual risk model in that it takes into account the time dimension and the specific policy structure including the premium payments. It is also different from classical risk theory in that it builds the risk process from micro-level contracts and parameters instead of assuming aggregated claim and premium processes outright. As a result, our approximating process behaves differently depending on the issued contract structure. We also illustrate the flexibility of our approach by formulating a finite-horizon ruin problem that incorporates actuarial reserve in the consideration.

This paper surveys recent techniques that have been developed for rare-event analysis of stochastic systems via simulation. We review standard (state-independent) techniques that take advantage of large deviations results for the design of efficient importance sampling estimators. Classical examples and counter-examples are discussed to illustrate the reach and limitations of the state-independent approach. Then we move to state-dependent techniques. These techniques can be applied to both light and heavy-tailed systems and are based on subsolutions (see e.g. Dupuis and Wang (2004) [5] , Dupuis and Wang (2007) [6] , Dupuis and Wang (2009) [80] , Dupuis et al. (2007) [7] ) and Lyapunov bounds (Blanchet and Glynn (2008) [9] , Blanchet et al. (2007) [11] , Blanchet (2009) [12] ). We briefly review the ideas behind these techniques, and provide several examples in which they are applicable.

Spectral library searching is an emerging approach in peptide identifications from tandem mass spectra, a critical step in proteomic data analysis. Conceptually, the premise of this approach is that the tandem MS fragmentation pattern of a peptide under some fixed conditions is a reproducible fingerprint of that peptide, such that unknown spectra acquired under the same conditions can be identified by spectral matching. In actual practice, a spectral library is first meticulously compiled from a large collection of previously observed and identified tandem MS spectra, usually obtained from shotgun proteomics experiments of complex mixtures. Then, a query spectrum is then identified by spectral matching using recently developed spectral search engines. This review discusses the basic principles of the two pillars of this approach: spectral library construction, and spectral library searching. An overview of the software tools available for these two tasks, as well as a high-level description of the underlying algorithms, will be given. Finally, several new methods that utilize spectral libraries for peptide identification in ways other than straightforward spectral matching will also be described.