Batch effect confounding leads to strong bias in performance estimates obtained by cross-validation.

BACKGROUND: With the large amount of biological data that is currently publicly available, many investigators combine multiple data sets to increase the sample size and potentially also the power of their analyses. However, technical differences ("batch effects") as well as differences in sample composition between the data sets may significantly affect the ability to draw generalizable conclusions from such studies. FOCUS: The current study focuses on the construction of classifiers, and the use of cross-validation to estimate their performance. In particular, we investigate the impact of batch effects and differences in sample composition between batches on the accuracy of the classification performance estimate obtained via cross-validation. The focus on estimation bias is a main difference compared to previous studies, which have mostly focused on the predictive performance and how it relates to the presence of batch effects. DATA: We work on simulated data sets. To have realistic intensity distributions, we use real gene expression data as the basis for our simulation. Random samples from this expression matrix are selected and assigned to group 1 (e.g., 'control') or group 2 (e.g., 'treated'). We introduce batch effects and select some features to be differentially expressed between the two groups. We consider several scenarios for our study, most importantly different levels of confounding between groups and batch effects. METHODS: We focus on well-known classifiers: logistic regression, Support Vector Machines (SVM), k-nearest neighbors (kNN) and Random Forests (RF). Feature selection is performed with the Wilcoxon test or the lasso. Parameter tuning and feature selection, as well as the estimation of the prediction performance of each classifier, is performed within a nested cross-validation scheme. The estimated classification performance is then compared to what is obtained when applying the classifier to independent data.

Measuring risk aversion with lists: A new bias

Various experimental procedures aimed at measuring individual risk aversion involve alist of pairs of alternative prospects. We first study the widely used method by Holt andLaury (2002), for which we find that the removal of some items from the lists yields asystematic decrease in risk aversion. This bias is quite distinct from other confoundsthat have been previously observed in the use of the Holt and Laury method. It may berelated to empirical phenomena and theoretical developments where better prospectsincrease risk aversion. Nevertheless, we have also found that the more recent elicitationmethod due to Abdellaoui et al. (2011), also based on lists, does not display anystatistically significant bias when the corresponding items of the list are removed. Ourresults suggest that methods other than the popular Holt and Laury one may bepreferable for the measurement of risk aversion.

Human Resource Information System Time Reporting System Guide for Individual Users, August 2009

Instructions for using the Human Resource Information System, for the State of Iowa.

ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting.

INTRODUCTION: The 2004 version of the World Health Organization classification subdivides thymic epithelial tumors into A, AB, B1, B2, and B3 (and rare other) thymomas and thymic carcinomas (TC). Due to a morphological continuum between some thymoma subtypes and some morphological overlap between thymomas and TC, a variable proportion of cases may pose problems in classification, contributing to the poor interobserver reproducibility in some studies. METHODS: To overcome this problem, hematoxylin-eosin-stained and immunohistochemically processed sections of prototypic, "borderland," and "combined" thymomas and TC (n = 72) were studied by 18 pathologists at an international consensus slide workshop supported by the International Thymic Malignancy Interest Group. RESULTS: Consensus was achieved on refined criteria for decision making at the A/AB borderland, the distinction between B1, B2, and B3 thymomas and the separation of B3 thymomas from TCs. "Atypical type A thymoma" is tentatively proposed as a new type A thymoma variant. New reporting strategies for tumors with more than one histological pattern are proposed. CONCLUSION: These guidelines can set the stage for reproducibility studies and the design of a clinically meaningful grading system for thymic epithelial tumors.

Fine-Tuning Translation Kinetics Selection as the Driving Force of Codon Usage Bias in the Hepatitis A Virus Capsid

Hepatitis A virus (HAV), the prototype of genus Hepatovirus, has several unique biological characteristics that distinguish it from other members of the Picornaviridae family. Among these, the need for an intact eIF4G factor for the initiation of translation results in an inability to shut down host protein synthesis by a mechanism similar to that of other picornaviruses. Consequently, HAV must inefficiently compete for the cellular translational machinery and this may explain its poor growth in cell culture. In this context of virus/cell competition, HAV has strategically adopted a naturally highly deoptimized codon usage with respect to that of its cellular host. With the aim to optimize its codon usage the virus was adapted to propagate in cells with impaired protein synthesis, in order to make tRNA pools more available for the virus. A significant loss of fitness was the immediate response to the adaptation process that was, however, later on recovered and more associated to a re-deoptimization rather than to an optimization of the codon usage specifically in the capsid coding region. These results exclude translation selection and instead suggest fine-tuning translation kinetics selection as the underlying mechanism of the codon usage bias in this specific genome region. Additionally, the results provide clear evidence of the Red Queen dynamics of evolution since the virus has very much evolved to re-adapt its codon usage to the environmental cellular changing conditions in order to recover the original fitness.

Relation for the nonequilibrium population of the interface states: effects on the bias dependence of the ideality factors

By an analysis of the exchange of carriers through a semiconductor junction, a general relationship for the nonequilibrium population of the interface states in Schottky barrier diodes has been derived. Based on this relationship, an analytical expression for the ideality factor valid in the whole range of applied bias has been given. This quantity exhibits two different behaviours depending on the value of the applied bias with respect to a critical voltage. This voltage, which depends on the properties of the interfacial layer, constitutes a new parameter to complete the characterization of these junctions. A simple interpretation of the different behaviours of the ideality factor has been given in terms of the nonequilibrium charging properties of interface states, which in turn explains why apparently different approaches have given rise to similar results. Finally, the relevance of our results has been considered on the determination of the density of interface states from nonideal current-voltage characteristics and in the evaluation of the effects of the interfacial layer thickness in metal-insulator-semiconductor tunnelling diodes.

Overweight and eating disorders in primary care: a sentinella reporting in 2-20 years old patients

Aims: To describe overweight or eating disorders in primary care consultations of Swiss children or adolescents and analyze responses by physicians. Methods: 150 to 200 primary care physicians participating in the Swiss Sentinel Surveillance Network in collaboration with the Swiss Federal Office of Public Health register their consultations over one year for selected health conditions. We describe reports of consultations where overweight or eating disorders were identified in subjects aged 2-20 years by physicians, patients or their relatives, or referring professionals, between 29.12.2007 and 15.2.2008. Results: 189 consultations were registered in the first 7 weeks of declaration. A short majority concerned female (58%) and 12-20 years old (53%) patients. Half were reported by pediatricians, one third by general practitioners and the remaining minority by internists. The sample included two thirds of Swiss-German and one third of Swiss-French cases. In the male subgroup aged 2-20 and in female children aged 2-11, almost all reported consultations were characterized by overweight. Among female teenagers, underweight was reported in 29% whilst overweight was recorded in 60%. Anorexia was noted in 68% of reported consultations of underweight female teenagers. In underweight patients, advice given by physicians frequently covered both nutrition and physical activity (38%) or nutrition only (29%), while no specific recommendations were recorded for the remaining third. In case of overweight, for one half of consultations patients received both nutritional and physical activity recommendations, for 12% nutritional only, and for one quarter patients were not advised in these domains. No specific treatment was usually proposed to overweight patients (65%), except when bulimia was diagnosed; in such case, one third of patients were proposed a psychological/psychiatric treatment, whereas both psychological and pharmacological treatments were frequently offered for underweight teenagers. Therapy was most often motivated by physicians (50%) or by relatives (44%), more rarely by patients themselves (7%). Conclusions: These preliminary data indicate that in some primary care consultations of young patients with overweight or eating disorders, advice was not given on nutrition and physical activity. This observation needs to be later confirmed with the totality of the consultations registered in 2008 and reasons will be further investigated.

Detection of bias in animal model pedigree indices of heifers

Selostus: Eläinmalliin perustuvien hiehojen odotusarvojen luotettavuus jalostusarvon ennusteena

CDL Self-Certification and Medical Examiner’s Certificate Reporting, December 9, 2011

Starting Jan. 30, 2012, the Iowa Department of Transportation (DOT) will implement new federal regulations that require all CDL holders and applicants to certify the type of driving they do, and require interstate CDL holders that carry a Medical Examiner’s Certificate to give the Iowa DOT a copy of their certificate, produced by the Iowa Department of Transportation.

Audit report on Internal Control over Financial Reporting of the State University of Iowa as of and for the year ended June 30, 2011

Audit report on Internal Control over Financial Reporting of the State University of Iowa as of and for the year ended June 30, 2011

Independent auditor’s report of the State of Iowa on internal control over financial reporting and on compliance and other matters based on an audit of financial statements performed in accordance with government auditing standards for the year ended June 30, 2011

Independent auditor’s report of the State of Iowa on internal control over financial reporting and on compliance and other matters based on an audit of financial statements performed in accordance with government auditing standards for the year ended June 30, 2011

Nicotine vaccines for smoking cessation.

BACKGROUND: By reducing the amount of nicotine that reaches the brain when a person smokes a cigarette, nicotine vaccines may help people to stop smoking or to prevent recent quitters from relapsing. OBJECTIVES: The aims of this review are to assess the efficacy of nicotine vaccines for smoking cessation and for relapse prevention, and to assess the frequency and type of adverse events associated with the use of nicotine vaccines. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Review Group specialised register for trials, using the term 'vaccine' in the title or abstract, or in a keyword (date of most recent search April 2012). To identify any other material including reviews and papers potentially relevant to the background or discussion sections, we also searched MEDLINE, EMBASE, and PsycINFO, combining terms for nicotine vaccines with terms for smoking and tobacco use, without design limits or limits for human subjects. We searched the Annual Meeting abstracts of the Society for Research on Nicotine and Tobacco up to 2012, using the search string 'vaccin'. We searched Google Scholar for 'nicotine vaccine'. We also searched company websites and Google for information related to specific vaccines. We searched clinicaltrials.gov in March 2012 for 'nicotine vaccine' and for the trade names of known vaccine candidates. SELECTION CRITERIA: We included randomized controlled trials of nicotine vaccines, at Phase II and Phase III trial stage and beyond, in adult smokers or recent ex-smokers. We included studies of nicotine vaccines used as part of smoking cessation or relapse prevention interventions. DATA COLLECTION AND ANALYSIS: We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, blinding of participants and personnel, reporting of outcomes, and completeness of follow-up.Our primary outcome measure was a minimum of six months abstinence from smoking. We used the most rigorous definition of abstinence, and preferred cessation rates at 12 months and biochemically validated rates where available. We have used the risk ratio (RR) to summarize individual trial outcomes. We have not pooled the current group of included studies as they cover different vaccines and variable regimens. MAIN RESULTS: There are no nicotine vaccines currently licensed for public use, but there are a number in development. We found four trials which met our inclusion criteria, three comparing NicVAX to placebo and one comparing NIC002 (formerly NicQbeta) to placebo. All were smoking cessation trials conducted by pharmaceutical companies as part of the drug development process, and all trials were judged to be at high or unclear risk of bias in at least one domain. Overall, 2642 smokers participated in the included studies in this review. None of the four included studies detected a statistically significant difference in long-term cessation between participants receiving vaccine and those receiving placebo. The RR for 12 month cessation in active and placebo groups was 1.35 (95% Confidence Interval (CI) 0.82 to 2.22) in the trial of NIC002 and 1.74 (95% CI 0.73 to 4.18) in one NicVAX trial. Two Phase III NicVAX trials, for which full results were not available, reported similar quit rates of approximately 11% in both groups. In the two studies with full results available, post hoc analyses detected higher cessation rates in participants with higher levels of nicotine antibodies, but these findings are not readily generalisable. The two studies with full results showed nicotine vaccines to be well tolerated, with the majority of adverse events classified as mild or moderate. In the study of NIC002, participants receiving the vaccine were more likely to report mild to moderate adverse events, most commonly flu-like symptoms, whereas in the study of NicVAX there was no significant difference between the two arms. Information on adverse events was not available for the large Phase III trials of NicVAX.Vaccine candidates are likely to undergo significant changes before becoming available to the general public, and those included in this review may not be the first to reach market; this limits the external validity of the results reported in this review in terms of both effectiveness and tolerability. AUTHORS' CONCLUSIONS: There is currently no evidence that nicotine vaccines enhance long-term smoking cessation. Rates of serious adverse events recorded in the two trials with full data available were low, and the majority of adverse events reported were at mild to moderate levels. The evidence available suggests nicotine vaccines do not induce compensatory smoking or affect withdrawal symptoms. No nicotine vaccines are currently licensed for use in any country but a number are under development.Further trials of nicotine vaccines are needed, comparing vaccines with placebo for smoking cessation. Further trials are also needed to explore the potential of nicotine vaccines to prevent relapse. Results from past, current and future research should be reported in full. Adverse events and serious adverse events should continue to be carefully monitored and thoroughly reported.