Assessment of the consistency and robustness of results from a multicenter trial of remission maintenance therapy for acute myeloid leukemia

<p>Abstract</p> <p>Background</p> <p>Data from a randomized multinational phase 3 trial of 320 adults with acute myeloid leukemia (AML) demonstrated that maintenance therapy with 3-week cycles of histamine dihydrochloride plus low-dose interleukin-2 (HDC/IL-2) for up to 18 months significantly improved leukemia-free survival (LFS) but lacked power to detect an overall survival (OS) difference.</p> <p>Purpose</p> <p>To assess the consistency of treatment benefit across patient subsets and the robustness of data with respect to trial centers and endpoints.</p> <p>Methods</p> <p>Forest plots were constructed with hazard ratios (HRs) of HDC/IL-2 treatment effects versus no treatment (control) for prospectively defined patient subsets. Inconsistency coefficients (I²) and interaction tests (X²) were used to detect any differences in benefit among subsets. Robustness of results to the elimination of individual study centers was performed using "leave-one-center-out" analyses. Associations between treatment effects on the endpoints were evaluated using weighted linear regression between HRs for LFS and OS estimated within countries.</p> <p>Results</p> <p>The benefit of HDC/IL-2 over controls was statistically consistent across all subsets defined by baseline prognostic variables. I²and <it>P</it>-values of X²ranged from 0.00 to 0.51 and 0.14 to 0.91, respectively. Treatment effects were statistically significant in 14 of 28 subsets analyzed. The "leave-one-center-out" analysis confirmed that no single center dominated (<it>P</it>-values ranged from 0.004 to 0.020 [mean 0.009]). The HRs representing the HDC/IL-2 effects on LFS and OS were strongly correlated at the country level (R²= 0.84).</p> <p>Limitations</p> <p>Small sample sizes in some of the subsets analyzed.</p> <p>Conclusions</p> <p>These analyses confirm the consistency and robustness of the HDC/IL-2 effect as compared with no treatment. LFS may be an acceptable surrogate for OS in future AML trials. Analyses of consistency and robustness may aid interpretation of data from multicenter trials, especially in populations with rare diseases, when the size of randomized clinical trials is limited.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00003991">NCT00003991</a></p

From unsupervised to semi-supervised adversarial domain adaptation in EEG-based sleep staging.

OBJECTIVE: The recent breakthrough of wearable sleep monitoring devices results in large amounts of sleep data. However, as limited labels are available, interpreting these data requires automated sleep stage classification methods with a small need for labeled training data. Transfer learning and domain adaptation offer possible solutions by enabling models to learn on a source dataset and adapt to a target dataset. APPROACH: In this paper, we investigate adversarial domain adaptation applied to real use cases with wearable sleep datasets acquired from diseased patient populations. Different practical aspects of the adversarial domain adaptation framework \hl{are examined}, including the added value of (pseudo-)labels from the target dataset and the influence of domain mismatch between the source and target data. The method is also implemented for personalization to specific patients. MAIN RESULTS: The results show that adversarial domain adaptation is effective in the application of sleep staging on wearable data. When compared to a model applied on a target dataset without any adaptation, the domain adaptation method in its simplest form achieves relative gains of 7%-27% in accuracy. The performance on the target domain is further boosted by adding pseudo-labels and real target domain labels when available, and by choosing an appropriate source dataset. Furthermore, unsupervised adversarial domain adaptation can also personalize a model, improving the performance by 1%-2% compared to a non-personal model. SIGNIFICANCE: In conclusion, adversarial domain adaptation provides a flexible framework for semi-supervised and unsupervised transfer learning. This is particularly useful in sleep staging and other wearable EEG applications

Diagnosing overtraining in athletes using the two-bout exercise protocol

Objective: In this work, whether a two-bout exercise protocol can be used to make an objective, immediately available distinction between non-functional over reaching (NFO) and overtraining syndrome (OTS) was studied. Design: Underperforming athletes who were diagnosed with the suspicion of NFO or OTS were included in the study. Recovery of the athletes was monitored by a sports physician to retrospectively distinguish NFO from OTS. Setting: Sports medicine laboratory Participants: The protocol was started and completed by 10 underperforming athletes. NFO was retrospectively diagnosed in five athletes, and OTS was diagnosed in five athletes. Interventions: A two-bout maximal exercise protocol was used to measure physical performance and stressinduced hormonal reactions. Main outcome measurements: Exercise duration, heart rate and blood lactate concentration were measured at the end of both exercise tests. Venous concentrations cortisol, adrenocorticotrophic hormone (ACTH), prolactin and growth hormone were measured both before and after both exercise tests. Results: Maximal blood lactate concentration was lower in OTS compared with NFO, while resting concentrations of cortisol, ACTH and prolactin concentrations were higher. However, sensitivity of these measures was low. The ACTH and prolactin reactions to the second exercise bout were much higher in NFO athletes compared with OTS and showed the highest sensitivity for making the distinction. Conclusions: NFO might be distinguished from OTS based on ACTH and prolactin reactions to a two-bout exercise protocol. This protocol could be a useful tool for diagnosing NFO and OTS; however, more data should be collected before this test can be used as the gold standard

Evaluation of Methods to Characterize the Change of the Respiratory Sinus Arrhythmia with Age in Sleep Apnea Patients

The High Frequency (HF) band of the power spectrum of the Heart Rate Variability (HRV) is widely accepted to contain information related to the respiration. However, it is known that this often results in misleading estimations of the strength of the Respiratory Sinus Arrhythmia (RSA). In this paper, different approaches to characterize the change of the RSA with age, combining HRV and respiratory signals, are studied. These approaches are the bandwidths in the power spectral density estimations, bivariate phase rectified signal averaging, information dynamics, a time-frequency representation, and a heart rate decomposition based on subspace projections. They were applied to a dataset of sleep apnea patients, specifically to periods without apneas and during NREM sleep. Each estimate reflected a different relationship between RSA and age, suggesting that they all capture the cardiorespiratory information in a different way. The comparison of the estimates indicates that the approaches based on the extraction of respiratory information from HRV provide a better characterization of the age-dependent degradation of the RSA

A literature review of the predictive validity of European dental school selection methods

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.Non peer reviewedPostprin

Surrogate markers and survival in women receiving first-line combination anthracycline chemotherapy for advanced breast cancer

Surrogate markers may help predict the effects of first-line treatment on survival. This metaregression analysis examines the relationship between several surrogate markers and survival in women with advanced breast cancer after receiving first-line combination anthracycline chemotherapy 5-fluorouracil, adriamycin and cyclophosphamide (FAC) or 5-fluorouracil, epirubicin and cyclophosphamide (FEC) . From a systematic literature review, we identified 42 randomised trials. The surrogate markers were complete or partial tumour response, progressive disease and time to progression. The treatment effect on survival was quantified by the hazard ratio. The treatment effect on each surrogate marker was quantified by the odds ratio (or ratio of median time to progression). The relationship between survival and each surrogate marker was assessed by a weighted linear regression of the hazard ratio against the odds ratio. There was a significant linear association between survival and complete or partial tumour response (P<0.001, R2=34%), complete tumour response (P=0.02, R2=12%), progressive disease (P<0.001, R2=38%) and time to progression (P<0.0001, R2=56%); R2 is the proportion of the variability in the treatment effect on survival that is explained by the treatment effect on the surrogate marker. Time to progression may be a useful surrogate marker for predicting survival in women receiving first-line anthracycline chemotherapy and could be used to estimate the survival benefit in future trials of first-line chemotherapy compared to FAC or FEC. The other markers, tumour response and progressive disease, were less good

Stronger diversity effects with increased environmental stress : a study of multitrophic interactions between oak, powdery mildew and ladybirds

Recent research has suggested that increasing neighbourhood tree species diversity may mitigate the impact of pests or pathogens by supporting the activities of their natural enemies and/or reducing the density of available hosts. In this study, we attempted to assess these mechanisms in a multitrophic study system of young oak (Quercus), oak powdery mildew (PM, caused by Erysiphe spp.) and a mycophagous ladybird (Psyllobora vigintiduo-punctata). We assessed ladybird mycophagy on oak PM in function of different neighbourhood tree species compositions. We also evaluated whether these species interactions were modulated by environmental conditions as suggested by the Stress Gradient Hypothesis. We adopted a complementary approach of a field experiment where we monitored oak saplings subjected to a reduced rainfall gradient in a young planted forest consisting of different tree species mixtures, as well as a lab experiment where we independently evaluated the effect of different watering treatments on PM infections and ladybird mycophagy. In the field experiment, we found effects of neighbourhood tree species richness on ladybird mycophagy becoming more positive as the target trees received less water. This effect was only found as weather conditions grew drier. In the lab experiment, we found a preference of ladybirds to graze on infected leaves from trees that received less water. We discuss potential mechanisms that might explain this preference, such as emissions of volatile leaf chemicals. Our results are in line with the expectations of the Natural Enemies Hypothesis and support the hypothesis that biodiversity effects become stronger with increased environmental stress

Predicting glioblastoma prognosis networks using weighted gene co-expression network analysis on TCGA data

<p>Abstract</p> <p>Background</p> <p>Using gene co-expression analysis, researchers were able to predict clusters of genes with consistent functions that are relevant to cancer development and prognosis. We applied a weighted gene co-expression network (WGCN) analysis algorithm on glioblastoma multiforme (GBM) data obtained from the TCGA project and predicted a set of gene co-expression networks which are related to GBM prognosis.</p> <p>Methods</p> <p>We modified the Quasi-Clique Merger algorithm (QCM algorithm) into edge-covering Quasi-Clique Merger algorithm (eQCM) for mining weighted sub-network in WGCN. Each sub-network is considered a set of features to separate patients into two groups using K-means algorithm. Survival times of the two groups are compared using log-rank test and Kaplan-Meier curves. Simulations using random sets of genes are carried out to determine the thresholds for log-rank test p-values for network selection. Sub-networks with p-values less than their corresponding thresholds were further merged into clusters based on overlap ratios (>50%). The functions for each cluster are analyzed using gene ontology enrichment analysis.</p> <p>Results</p> <p>Using the eQCM algorithm, we identified 8,124 sub-networks in the WGCN, out of which 170 sub-networks show p-values less than their corresponding thresholds. They were then merged into 16 clusters.</p> <p>Conclusions</p> <p>We identified 16 gene clusters associated with GBM prognosis using the eQCM algorithm. Our results not only confirmed previous findings including the importance of cell cycle and immune response in GBM, but also suggested important epigenetic events in GBM development and prognosis.</p

Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists

<p>Abstract</p> <p>Background</p> <p>Overall survival (OS) is the gold standard for the demonstration of a clinical benefit in cancer trials. Replacement of OS by a surrogate endpoint allows to reduce trial duration. To date, few surrogate endpoints have been validated in digestive oncology. The aim of this study was to draw up an ordered list of potential surrogate endpoints for OS in digestive cancer trials, by way of a survey among clinicians and methodologists. Secondary objective was to obtain their opinion on surrogacy and quality of life (QoL).</p> <p>Methods</p> <p>In 2007 and 2008, self administered sequential questionnaires were sent to a panel of French clinicians and methodologists involved in the conduct of cancer clinical trials. In the first questionnaire, panellists were asked to choose the most important characteristics defining a surrogate among six proposals, to give advantages and drawbacks of the surrogates, and to answer questions about their validation and use. Then they had to suggest potential surrogate endpoints for OS in each of the following tumour sites: oesophagus, stomach, liver, pancreas, biliary tract, lymphoma, colon, rectum, and anus. They finally gave their opinion on QoL as surrogate endpoint. In the second questionnaire, they had to classify the previously proposed candidate surrogates from the most (position #1) to the least relevant in their opinion.</p> <p>Frequency at which the endpoints were chosen as first, second or third most relevant surrogates was calculated and served as final ranking.</p> <p>Results</p> <p>Response rate was 30% (24/80) in the first round and 20% (16/80) in the second one. Participants highlighted key points concerning surrogacy. In particular, they reminded that a surrogate endpoint is expected to predict clinical benefit in a well-defined therapeutic situation. Half of them thought it was not relevant to study QoL as surrogate for OS.</p> <p>DFS, in the neoadjuvant settings or early stages, and PFS, in the non operable or metastatic settings, were ranked first, with a frequency of more than 69% in 20 out of 22 settings. PFS was proposed in association with QoL in metastatic primary liver and stomach cancers (both 81%). This composite endpoint was ranked second in metastatic oesophageal (69%), colorectal (56%) and anal (56%) cancers, whereas QoL alone was also suggested in most metastatic situations.</p> <p>Other endpoints frequently suggested were R0 resection in the neoadjuvant settings (oesophagus (69%), stomach (56%), pancreas (75%) and biliary tract (63%)) and response. An unexpected endpoint was metastatic PFS in non operable oesophageal (31%) and pancreatic (44%) cancers. Quality and results of surgical procedures like sphincter preservation were also cited as eligible surrogate endpoints in rectal (19%) and anal (50% in case of localized disease) cancers. Except for alpha-FP kinetic in hepatocellular carcinoma (13%) and CA19-9 decline (6%) in pancreas, few endpoints based on biological or tumour markers were proposed.</p> <p>Conclusion</p> <p>The overall results should help prioritise the endpoints to be statistically evaluated as surrogate for OS, so that trialists and clinicians can rely on endpoints that ensure relevant clinical benefit to the patient.</p

A Model for Promoting Poultry Industry Development in Togo: Part 1. Management Practices and Incubation Conditions

In commercial poultry husbandry practice, the hatchery takes over the incubation of bird eggs in order to provide as many day-old chicks as needed at any time to farmers. The main bottleneck for poultry industry development in Togo is the lack of day-old chick supply. Indeed, there is no proficient hatchery which can cover the needs of the farmers because of lack of information about hatchery management or people trained as hatchery managers. Also, there is lack of information about management practice aspects, etc. With the aim to promote poultry industry in Togo, an interuniversity project [Catholic University of Leuven (KUL) and University of Lome (UL)] as a model of poultry industry development was implemented. Specific objectives of the current project are to implement research and development activities on better conditions of incubation and adapted management practices focusing mainly on (1) Effect of early transferring of layer breeders hatching eggs on embryo parameters and hatchability, (2) Comparison of different chicken genotypes in Embryo Physiology, (3) Effects of heat conditioning at d 16 to 18 of incubation or during early broiler rearing on embryo physiology, post-hatch growth performance and heat tolerance, (4) Effect of low albumen quantity on chick embryo and post-hatch parameters, (5) Effects of In ovo-administration of L-carnitine on hatching events and juvenile performance of layer-type chick, (6) Interaction effects of mixing hatching eggs of differential embryo growth trajectory and incubator CO2 concentration on embryo physiological parameters, (7) Effect of delayed feed access on production and blood parameters of layer-type chicks and (8) Induced moulting of layer chickens