Effect of training-sample size and classification difficulty on the accuracy of genomic predictors.

Introduction: As part of the MicroArray Quality Control (MAQC)-II project, this analysis examines how the choice of univariate feature-selection methods and classification algorithms may influence the performance of genomic predictors under varying degrees of prediction difficulty represented by three clinically relevant endpoints. Methods: We used gene-expression data from 230 breast cancers (grouped into training and independent validation sets), and we examined 40 predictors (five univariate feature-selection methods combined with eight different classifiers) for each of the three endpoints. Their classification performance was estimated on the training set by using two different resampling methods and compared with the accuracy observed in the independent validation set. Results: A ranking of the three classification problems was obtained, and the performance of 120 models was estimated and assessed on an independent validation set. The bootstrapping estimates were closer to the validation performance than were the cross-validation estimates. The required sample size for each endpoint was estimated, and both gene-level and pathway-level analyses were performed on the obtained models. Conclusions: We showed that genomic predictor accuracy is determined largely by an interplay between sample size and classification difficulty. Variations on univariate feature-selection methods and choice of classification algorithm have only a modest impact on predictor performance, and several statistically equally good predictors can be developed for any given classification problem.

Detecting and measuring deprivation in primary care: development, reliability and validity of a self-reported questionnaire: the DiPCare-Q.

OBJECTIVES: Advances in biopsychosocial science have underlined the importance of taking social history and life course perspective into consideration in primary care. For both clinical and research purposes, this study aims to develop and validate a standardised instrument measuring both material and social deprivation at an individual level. METHODS: We identified relevant potential questions regarding deprivation using a systematic review, structured interviews, focus group interviews and a think-aloud approach. Item response theory analysis was then used to reduce the length of the 38-item questionnaire and derive the deprivation in primary care questionnaire (DiPCare-Q) index using data obtained from a random sample of 200 patients during their planned visits to an ambulatory general internal medicine clinic. Patients completed the questionnaire a second time over the phone 3 days later to enable us to assess reliability. Content validity of the DiPCare-Q was then assessed by 17 general practitioners. Psychometric properties and validity of the final instrument were investigated in a second set of patients. The DiPCare-Q was administered to a random sample of 1898 patients attending one of 47 different private primary care practices in western Switzerland along with questions on subjective social status, education, source of income, welfare status and subjective poverty. RESULTS: Deprivation was defined in three distinct dimensions: material (eight items), social (five items) and health deprivation (three items). Item consistency was high in both the derivation (Kuder-Richardson Formula 20 (KR20) =0.827) and the validation set (KR20 =0.778). The DiPCare-Q index was reliable (interclass correlation coefficients=0.847) and was correlated to subjective social status (r(s)=-0.539). CONCLUSION: The DiPCare-Q is a rapid, reliable and validated instrument that may prove useful for measuring both material and social deprivation in primary care.

Plasma Level of Mmp-9 as Predictive Factor for Response and Progression Free Survival in Patients Treated with Bevacizumab (Bev) and Pegylated Liposomal Doxorubicin (Pld): Sakk 24/06

Background: There is currently no identified marker predicting benefit from Bev in patients with breast cancer (pts). We monitored prospectively 6 angiogenesis-related factors in the blood of advanced stage pts treated with a combination of Bev and PLD in a phase II trial of the Swiss Group for Clinical Cancer Research, SAKK.Methods: Pts received PLD (20 mg/m2) and Bev (10 mg/kg) every 2 weeks for a maximum of 12 administrations, followed by Bev monotherapy until progression or severe toxicity. Blood samples were collected at baseline, during treatment and at treatment discontinuation. Enzyme-linked immunosorbent assays (Quantikine, R&DSystems and Reliatech) were used to measure vascular endothelial growth factor (VEGF), placental growth factor (PlGF), matrix metalloproteinase 9 (MMP-9) and soluble VEGF receptors -1, -2 and -3. The natural log-transformed (ln) data for each factor was analyzed by analysis of variance (ANOVA) model to investigate differences between the mean values of the subgroups of interest (where a = 0.05), based on the best tumor response by RECIST.Results: 132 samples were collected in 41 pts. The mean of baseline ln MMP-9 levels was significantly lower in pts with tumor progression than those with tumor response (p=0.0202, log fold change=0.8786) or disease control (p=0.0035, log fold change=0.8427). Higher MMP-9 level was a significant predictor of superior progression free survival (PFS): p=0.0417, hazard ratio=0.574, 95% CI=0.336-0.979. In a multivariate cox proportional hazards model, containing performance status, disease free interval, number of tumor sites, visceral involvement and prior adjuvant chemotherapy, using stepwise regression baseline MMP-9 was still a statistically 117P Table 1. SOLTI-0701* AC01B07* NU07B1* SOR+CAP N=20 PL+CAP N=33 SOR+ GEM/CAP N=23 PL+ GEM/CAP N=27 SOR+PAC N=48 PL+PAC N=46 Baseline characteristics Age, median (range), y 49 (32-72) 53 (30-78 54 (32-69) 57 (31-82) 50 (27-80) 52 (23-74) AJCC stage, n (%) IIIB/IIIC 3 (15) 6 (18) 0 (0) 3 (11) 8 (17) 9 (20) IV 17 (85) 27 (82) 23 (100) 24 (89) 40 (83) 37 (80) Metastatic site, n (%) Non-visceral 3 (15) 6 (18) 7 (30) 6 (22) 9 (19) 17 (37) Visceral 17 (85) 27 (82) 16 (70) 21 (78) 39 (81) 29 (63) Prior metastatic chemo, n (%) 8 (40) 15 (45) 21 (91) 25 (93) - - Efficacy PFS, median, mo 4.3 2.5 3.1 2.6 5.6 5.5 HR (95% CI)_ 0.60 (0.31, 1.14) 0.57 (0.30, 1.09) 0.86 (0.50, 1.45) 1-sided P value_ 0.055 0.044 0.281 Overall survival, median, mo 17.5 16.1 Pending 14.7 18.2 HR (95% CI)_ 0.98 (0.50, 1.89) 1.11 (0.64, 1.94) 1-sided P value_ 0.476 0.352 Safety N=20 N=33 N=22 N=27 N=46 N=46 Tx-emergent Grade 3/4, n (%) 15 (75) 16 (48) 20 (91) 17 (63) 36 (78) 16 (35) Grade 3§ hand-foot skin reaction/ syndrome 8 (40) 5 (15) 8 (36) 0 (0) 14 (30) 2 (4) *Efficacy results based on intent-to-treat population and safety results based on safety population (pts who received study drug[s]); _Cox regression within each subgroup; _log-rank test within each subgroup; §maximum toxicity grade for hand-foot skin reaction/syndrome; AJCC, American Joint Committee on Cancer mittedabstractsª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com Downloaded from annonc.oxfordjournals.org at Bibliotheque Cantonale et Universitaire on June 6, 2011 significant factor (p=0.0266). The results of the other measured factors were presented elsewhere.Conclusions: Higher levels of MMP-9 could predict tumor response and superior PFSin pts treated with a combination of Bev and PLD. These exploratory results justify further investigations of MMP-9 in pts treated with Bev combinations in order to assess its role as a prognostic and predictive factor.Disclosure: K. Zaman: Participation in advisory board of Roche; partial sponsoring ofthe study by Roche (the main sponsor was the Swiss Federation against Cancer (Oncosuisse)). B. Thu¨rlimann: stock of Roche; Research grants from Roche. R. vonMoos: Participant of Advisory Board and Speaker honoraria

Generating controlled image sets in cognitive neuroscience research.

The investigation of perceptual and cognitive functions with non-invasive brain imaging methods critically depends on the careful selection of stimuli for use in experiments. For example, it must be verified that any observed effects follow from the parameter of interest (e.g. semantic category) rather than other low-level physical features (e.g. luminance, or spectral properties). Otherwise, interpretation of results is confounded. Often, researchers circumvent this issue by including additional control conditions or tasks, both of which are flawed and also prolong experiments. Here, we present some new approaches for controlling classes of stimuli intended for use in cognitive neuroscience, however these methods can be readily extrapolated to other applications and stimulus modalities. Our approach is comprised of two levels. The first level aims at equalizing individual stimuli in terms of their mean luminance. Each data point in the stimulus is adjusted to a standardized value based on a standard value across the stimulus battery. The second level analyzes two populations of stimuli along their spectral properties (i.e. spatial frequency) using a dissimilarity metric that equals the root mean square of the distance between two populations of objects as a function of spatial frequency along x- and y-dimensions of the image. Randomized permutations are used to obtain a minimal value between the populations to minimize, in a completely data-driven manner, the spectral differences between image sets. While another paper in this issue applies these methods in the case of acoustic stimuli (Aeschlimann et al., Brain Topogr 2008), we illustrate this approach here in detail for complex visual stimuli.

The impact of iron supplementation efficiency in female blood donors with a decreased ferritin level and no anaemia. Rationale and design of a randomised controlled trial: a study protocol.

ABSTRACT: BACKGROUND: There is no recommendation to screen ferritin level in blood donors, even though several studies have noted the high prevalence of iron deficiency after blood donation, particularly among menstruating females. Furthermore, some clinical trials have shown that non-anaemic women with unexplained fatigue may benefit from iron supplementation. Our objective is to determine the clinical effect of iron supplementation on fatigue in female blood donors without anaemia, but with a mean serum ferritin </= 30 ng/ml. METHODS/DESIGN: In a double blind randomised controlled trial, we will measure blood count and ferritin level of women under age 50 yr, who donate blood to the University Hospital of Lausanne Blood Transfusion Department, at the time of the donation and after 1 week. One hundred and forty donors with a ferritin level </= 30 ng/ml and haemoglobin level >/= 120 g/l (non-anaemic) a week after the donation will be included in the study and randomised. A one-month course of oral ferrous sulphate (80 mg/day of elemental iron) will be introduced vs. placebo. Self-reported fatigue will be measured using a visual analogue scale. Secondary outcomes are: score of fatigue (Fatigue Severity Scale), maximal aerobic power (Chester Step Test), quality of life (SF-12), and mood disorders (Prime-MD). Haemoglobin and ferritin concentration will be monitored before and after the intervention. DISCUSSION: Iron deficiency is a potential problem for all blood donors, especially menstruating women. To our knowledge, no other intervention study has yet evaluated the impact of iron supplementation on subjective symptoms after a blood donation. TRIAL REGISTRATION: NCT00689793.

The level of infestation with the vector of cattle babesiosis in Argentina

Studies were carried out to determine the differential aptitude to sustain the only vector of cattle babesiosis in Argentina, the tick Boophilus microplus, throughout the infested region of this country. Tick counts on Bos taurus cattle were used as the main criterion to classify favourable (F), intermediate (I) and unfavourable (U) areas for its development. The geographical limits of each area set up using data of non-parasitic tick stages, temperature, water balance and map recognition of flooded and unflooded zones. The F area contained 16.5 x 10 (elevado a sexta potência) ha with a cattle population of 6 x 10 (elevado a sexta potência); the I and U areas had 25 x 10 (elevado a sexta potência ha with 2.7 x 10 (elevado a sexta potência) cattle and 198 x 10 (elevado a sexta potência) with population of 2.4 x 10(elevado a sexta potência) cattle, respectively. Research on the relationship amongst Babesia-Boophilus-cattle is needed in the F area for tick development which coincides with the best region for cattle breeding.

Context-dependent interpretation of the prognostic value of BRAF and KRAS mutations in colorectal cancer.

BACKGROUND: The mutation status of the BRAF and KRAS genes has been proposed as prognostic biomarker in colorectal cancer. Of them, only the BRAF V600E mutation has been validated independently as prognostic for overall survival and survival after relapse, while the prognostic value of KRAS mutation is still unclear. We investigated the prognostic value of BRAF and KRAS mutations in various contexts defined by stratifications of the patient population. METHODS: We retrospectively analyzed a cohort of patients with stage II and III colorectal cancer from the PETACC-3 clinical trial (N = 1,423), by assessing the prognostic value of the BRAF and KRAS mutations in subpopulations defined by all possible combinations of the following clinico-pathological variables: T stage, N stage, tumor site, tumor grade and microsatellite instability status. In each such subpopulation, the prognostic value was assessed by log rank test for three endpoints: overall survival, relapse-free survival, and survival after relapse. The significance level was set to 0.01 for Bonferroni-adjusted p-values, and a second threshold for a trend towards statistical significance was set at 0.05 for unadjusted p-values. The significance of the interactions was tested by Wald test, with significance level of 0.05. RESULTS: In stage II-III colorectal cancer, BRAF mutation was confirmed a marker of poor survival only in subpopulations involving microsatellite stable and left-sided tumors, with higher effects than in the whole population. There was no evidence for prognostic value in microsatellite instable or right-sided tumor groups. We found that BRAF was also prognostic for relapse-free survival in some subpopulations. We found no evidence that KRAS mutations had prognostic value, although a trend was observed in some stratifications. We also show evidence of heterogeneity in survival of patients with BRAF V600E mutation. CONCLUSIONS: The BRAF mutation represents an additional risk factor only in some subpopulations of colorectal cancers, in others having limited prognostic value. However, in the subpopulations where it is prognostic, it represents a marker of much higher risk than previously considered. KRAS mutation status does not seem to represent a strong prognostic variable.

Large multi-gene phylogenetic trees of the grasses (Poaceae): progress towards complete tribal and generic level sampling.

In this paper we included a very broad representation of grass family diversity (84% of tribes and 42% of genera). Phylogenetic inference was based on three plastid DNA regions rbcL, matK and trnL-F, using maximum parsimony and Bayesian methods. Our results resolved most of the subfamily relationships within the major clades (BEP and PACCMAD), which had previously been unclear, such as, among others the: (i) BEP and PACCMAD sister relationship, (ii) composition of clades and the sister-relationship of Ehrhartoideae and Bambusoideae + Pooideae, (iii) paraphyly of tribe Bambuseae, (iv) position of Gynerium as sister to Panicoideae, (v) phylogenetic position of Micrairoideae. With the presence of a relatively large amount of missing data, we were able to increase taxon sampling substantially in our analyses from 107 to 295 taxa. However, bootstrap support and to a lesser extent Bayesian inference posterior probabilities were generally lower in analyses involving missing data than those not including them. We produced a fully resolved phylogenetic summary tree for the grass family at subfamily level and indicated the most likely relationships of all included tribes in our analysis.

Coronary heart disease in primary care: accuracy of medical history and physical findings in patients with chest pain - a study protocol for a systematic review with individual patient data.

BACKGROUND: Chest pain is a common complaint in primary care, with coronary heart disease (CHD) being the most concerning of many potential causes. Systematic reviews on the sensitivity and specificity of symptoms and signs summarize the evidence about which of them are most useful in making a diagnosis. Previous meta-analyses are dominated by studies of patients referred to specialists. Moreover, as the analysis is typically based on study-level data, the statistical analyses in these reviews are limited while meta-analyses based on individual patient data can provide additional information. Our patient-level meta-analysis has three unique aims. First, we strive to determine the diagnostic accuracy of symptoms and signs for myocardial ischemia in primary care. Second, we investigate associations between study- or patient-level characteristics and measures of diagnostic accuracy. Third, we aim to validate existing clinical prediction rules for diagnosing myocardial ischemia in primary care. This article describes the methods of our study and six prospective studies of primary care patients with chest pain. Later articles will describe the main results. METHODS/DESIGN: We will conduct a systematic review and IPD meta-analysis of studies evaluating the diagnostic accuracy of symptoms and signs for diagnosing coronary heart disease in primary care. We will perform bivariate analyses to determine the sensitivity, specificity and likelihood ratios of individual symptoms and signs and multivariate analyses to explore the diagnostic value of an optimal combination of all symptoms and signs based on all data of all studies. We will validate existing clinical prediction rules from each of the included studies by calculating measures of diagnostic accuracy separately by study. DISCUSSION: Our study will face several methodological challenges. First, the number of studies will be limited. Second, the investigators of original studies defined some outcomes and predictors differently. Third, the studies did not collect the same standard clinical data set. Fourth, missing data, varying from partly missing to fully missing, will have to be dealt with.Despite these limitations, we aim to summarize the available evidence regarding the diagnostic accuracy of symptoms and signs for diagnosing CHD in patients presenting with chest pain in primary care. REVIEW REGISTRATION: Centre for Reviews and Dissemination (University of York): CRD42011001170.

Rehabilitation needs assessment in persons with spinal cord injury following the 2010 earthquake in Haiti: a pilot study using an ICF-based tool.

OBJECTIVE: The aim of this pilot study was to describe problems in functioning and associated rehabilitation needs in persons with spinal cord injury after the 2010 earthquake in Haiti by applying a newly developed tool based on the International Classification of Functioning, Disability and Health (ICF). DESIGN: Pilot study. SUBJECTS: Eighteen persons with spinal cord injury (11 women, 7 men) participated in the needs assessment. Eleven patients had complete lesions (American Spinal Injury Association Impairment Scale; AIS A), one patient had tetraplegia. METHODS: Data collection included information from the International Spinal Cord Injury Core Data Set and a newly developed needs assessment tool based on ICF Core Sets. This tool assesses the level of functioning, the corresponding rehabilitation need, and required health professional. Data were summarized using descriptive statistics. RESULTS: In body functions and body structures, patients showed typical problems following spinal cord injury. Nearly all patients showed limitations and restrictions in their activities and participation related to mobility, self-care and aspects of social integration. Several environmental factors presented barriers to these limitations and restrictions. However, the availability of products and social support were identified as facilitators. Rehabilitation needs were identified in nearly all aspects of functioning. To address these needs, a multidisciplinary approach would be needed. CONCLUSION: This ICF-based needs assessment provided useful information for rehabilitation planning in the context of natural disaster. Future studies are required to test and, if necessary, adapt the assessment.

The problem of the competitiveness of nuclear energy: a biophysical explanation

In this study I try to explain the systemic problem of the low economic competitiveness of nuclear energy for the production of electricity by carrying out a biophysical analysis of its production process. Given the fact that neither econometric approaches nor onedimensional methods of energy analyses are effective, I introduce the concept of biophysical explanation as a quantitative analysis capable of handling the inherent ambiguity associated with the concept of energy. In particular, the quantities of energy, considered as relevant for the assessment, can only be measured and aggregated after having agreed on a pre-analytical definition of a grammar characterizing a given set of finite transformations. Using this grammar it becomes possible to provide a biophysical explanation for the low economic competitiveness of nuclear energy in the production of electricity. When comparing the various unit operations of the process of production of electricity with nuclear energy to the analogous unit operations of the process of production of fossil energy, we see that the various phases of the process are the same. The only difference is related to characteristics of the process associated with the generation of heat which are completely different in the two systems. Since the cost of production of fossil energy provides the base line of economic competitiveness of electricity, the (lack of) economic competitiveness of the production of electricity from nuclear energy can be studied, by comparing the biophysical costs associated with the different unit operations taking place in nuclear and fossil power plants when generating process heat or net electricity. In particular, the analysis focuses on fossil-fuel requirements and labor requirements for those phases that both nuclear plants and fossil energy plants have in common: (i) mining; (ii) refining/enriching; (iii) generating heat/electricity; (iv) handling the pollution/radioactive wastes. By adopting this approach, it becomes possible to explain the systemic low economic competitiveness of nuclear energy in the production of electricity, because of: (i) its dependence on oil, limiting its possible role as a carbon-free alternative; (ii) the choices made in relation to its fuel cycle, especially whether it includes reprocessing operations or not; (iii) the unavoidable uncertainty in the definition of the characteristics of its process; (iv) its large inertia (lack of flexibility) due to issues of time scale; and (v) its low power level.

Antimalarial Drug Resistance: Surveillance and Molecular Methods for National Malaria Control Programmes

National malaria control programmes have the responsibility to develop a policy for malaria disease management based on a set of defined criteria as efficacy, side effects, costs and compliance. These will fluctuate over time and national guidelines will require periodic re-assessment and revision. Changing a drug policy is a major undertaking that can take several years before being fully operational. The standard methods on which a decision can be taken are the in vivo and the in vitro tests. The latter allow a quantitative measurement of the drug response and the assessment of several drugs at once. However, in terms of drug policy change its results might be difficult to interpret although they may be used as an early warning system for 2nd or 3rd line drugs. The new WHO 14-days in vivo test addresses mainly the problem of treatment failure and of haematological parameters changes in sick children. It gives valuable information on whether a drug still `works'. None of these methods are well suited for large-scale studies. Molecular methods based on detection of mutations in parasite molecules targeted by antimalarial drugs could be attractive tools for surveillance. However, their relationship with in vivo test results needs to be established

Systematics and Population Level Analysis of Anopheles darlingi

A new phylogenetic analysis of the Nyssorhynchus subgenus (Danoff-Burg and Conn, unpub. data) using six data sets {morphological (all life stages); scanning electron micrographs of eggs; nuclear ITS2 sequences; mitochondrial COII, ND2 and ND6 sequences} revealed different topologies when each data set was analyzed separately but no heterogeneity between the data sets using the arn test. Consequently, the most accurate estimate of the phylogeny was obtained when all the data were combined. This new phylogeny supports a monophyletic Nyssorhynchus subgenus but both previously recognized sections in the subgenus (Albimanus and Argyritarsis) were demonstrated to be paraphyletic relative to each other and four of the seven clades included species previously placed in both sections. One of these clades includes both Anopheles darlingi and An. albimanus, suggesting that the ability to vector malaria effectively may have originated once in this subgenus. Both a conserved (315 bp) and a variable (425 bp) region of the mitochondrial COI gene from 15 populations of An. darlingi from Belize, Bolivia, Brazil, French Guiana, Peru and Venezuela were used to examine the evolutionary history of this species and to test several analytical assumptions. Results demonstrated (1) parsimony analysis is equally informative compared to distance analysis using NJ; (2) clades or clusters are more strongly supported when these two regions are combined compared to either region separately; (3) evidence (in the form of remnants of older haplotype lineages) for two colonization events; and (4) significant genetic divergence within the population from Peixoto de Azevedo (State of Mato Grosso, Brazil). The oldest lineage includes populations from Peixoto, Boa Vista (State of Roraima) and Dourado (State of São Paulo).

Local-global splitting for spatiotemporal-adaptive multiscale methods

We present a novel spatiotemporal-adaptive Multiscale Finite Volume (MsFV) method, which is based on the natural idea that the global coarse-scale problem has longer characteristic time than the local fine-scale problems. As a consequence, the global problem can be solved with larger time steps than the local problems. In contrast to the pressure-transport splitting usually employed in the standard MsFV approach, we propose to start directly with a local-global splitting that allows to locally retain the original degree of coupling. This is crucial for highly non-linear systems or in the presence of physical instabilities. To obtain an accurate and efficient algorithm, we devise new adaptive criteria for global update that are based on changes of coarse-scale quantities rather than on fine-scale quantities, as it is routinely done before in the adaptive MsFV method. By means of a complexity analysis we show that the adaptive approach gives a noticeable speed-up with respect to the standard MsFV algorithm. In particular, it is efficient in case of large upscaling factors, which is important for multiphysics problems. Based on the observation that local time stepping acts as a smoother, we devise a self-correcting algorithm which incorporates the information from previous times to improve the quality of the multiscale approximation. We present results of multiphase flow simulations both for Darcy-scale and multiphysics (hybrid) problems, in which a local pore-scale description is combined with a global Darcy-like description. The novel spatiotemporal-adaptive multiscale method based on the local-global splitting is not limited to porous media flow problems, but it can be extended to any system described by a set of conservation equations.

Patient-ventilator asynchrony during non-invasive ventilation for acute respiratory failure: a multicenter study.

OBJECTIVE : To determine the prevalence of patient-ventilator asynchrony in patients receiving non-invasive ventilation (NIV) for acute respiratory failure. DESIGN : Prospective multicenter observation study. SETTING : Intensive care units in three university hospitals. METHODS: Patients consecutively admitted to ICU were included. NIV, performed with an ICU ventilator, was set by the clinician. Airway pressure, flow, and surface diaphragmatic electromyography were recorded continuously for 30 min. Asynchrony events and the asynchrony index (AI) were determined from visual inspection of the recordings and clinical observation. RESULTS: A total of 60 patients were included, 55% of whom were hypercapnic. Auto-triggering was present in 8 (13%) patients, double triggering in 9 (15%), ineffective breaths in 8 (13%), premature cycling 7 (12%) and late cycling in 14 (23%). An AI > 10%, indicating severe asynchrony, was present in 26 patients (43%), whose median (25-75 IQR) AI was 26 (15-54%). A significant correlation was found between the magnitude of leaks and the number of ineffective breaths and severity of delayed cycling. Multivariate analysis indicated that the level of pressure support and the magnitude of leaks were weakly, albeit significantly, associated with an AI > 10%. Patient comfort scale was higher in pts with an AI < 10%. CONCLUSION: Patient-ventilator asynchrony is common in patients receiving NIV for acute respiratory failure. Our results suggest that leaks play a major role in generating patient-ventilator asynchrony and discomfort, and point the way to further research to determine if ventilator functions designed to cope with leaks can reduce asynchrony in the clinical setting.