GSVA: gene set variation analysis for microarray and RNA-seq data

Gene set enrichment (GSE) analysis is a popular framework for condensing information from gene expression profiles into a pathway or signature summary. The strengths of this approach over single gene analysis include noise and dimension reduction, as well as greater biological interpretability. As molecular profiling experiments move beyond simple case-control studies, robust and flexible GSE methodologies are needed that can model pathway activity within highly heterogeneous data sets. To address this challenge, we introduce Gene Set Variation Analysis (GSVA), a GSE method that estimates variation of pathway activity over a sample population in an unsupervised manner. We demonstrate the robustness of GSVA in a comparison with current state of the art sample-wise enrichment methods. Further, we provide examples of its utility in differential pathway activity and survival analysis. Lastly, we show how GSVA works analogously with data from both microarray and RNA-seq experiments. GSVA provides increased power to detect subtle pathway activity changes over a sample population in comparison to corresponding methods. While GSE methods are generally regarded as end points of a bioinformatic analysis, GSVA constitutes a starting point to build pathway-centric models of biology. Moreover, GSVA contributes to the current need of GSE methods for RNA-seq data. GSVA is an open source software package for R which forms part of the Bioconductor project and can be downloaded at http://www.bioconductor.org.

The QUASAR reproducibility study, Part II: Results from a multi-center Arterial Spin Labeling test-retest study.

Arterial Spin Labeling (ASL) is a method to measure perfusion using magnetically labeled blood water as an endogenous tracer. Being fully non-invasive, this technique is attractive for longitudinal studies of cerebral blood flow in healthy and diseased individuals, or as a surrogate marker of metabolism. So far, ASL has been restricted mostly to specialist centers due to a generally low SNR of the method and potential issues with user-dependent analysis needed to obtain quantitative measurement of cerebral blood flow (CBF). Here, we evaluated a particular implementation of ASL (called Quantitative STAR labeling of Arterial Regions or QUASAR), a method providing user independent quantification of CBF in a large test-retest study across sites from around the world, dubbed "The QUASAR reproducibility study". Altogether, 28 sites located in Asia, Europe and North America participated and a total of 284 healthy volunteers were scanned. Minimal operator dependence was assured by using an automatic planning tool and its accuracy and potential usefulness in multi-center trials was evaluated as well. Accurate repositioning between sessions was achieved with the automatic planning tool showing mean displacements of 1.87+/-0.95 mm and rotations of 1.56+/-0.66 degrees . Mean gray matter CBF was 47.4+/-7.5 [ml/100 g/min] with a between-subject standard variation SD(b)=5.5 [ml/100 g/min] and a within-subject standard deviation SD(w)=4.7 [ml/100 g/min]. The corresponding repeatability was 13.0 [ml/100 g/min] and was found to be within the range of previous studies.

Optimization of Snow Drifting Mitigation and Control Methods for Iowa Conditions Part II, TR-626, 2015

Blowing and drifting of snow is a major concern for transportation efficiency and road safety in regions where their development is common. One common way to mitigate snow drift on roadways is to install plastic snow fences. Correct design of snow fences is critical for road safety and maintaining the roads open during winter in the US Midwest and other states affected by large snow events during the winter season and to maintain costs related to accumulation of snow on the roads and repair of roads to minimum levels. Of critical importance for road safety is the protection against snow drifting in regions with narrow rights of way, where standard fences cannot be deployed at the recommended distance from the road. Designing snow fences requires sound engineering judgment and a thorough evaluation of the potential for snow blowing and drifting at the construction site. The evaluation includes site-specific design parameters typically obtained with semi-empirical relations characterizing the local transport conditions. Among the critical parameters involved in fence design and assessment of their post-construction efficiency is the quantification of the snow accumulation at fence sites. The present study proposes a joint experimental and numerical approach to monitor snow deposits around snow fences, quantitatively estimate snow deposits in the field, asses the efficiency and improve the design of snow fences. Snow deposit profiles were mapped using GPS based real-time kinematic surveys (RTK) conducted at the monitored field site during and after snow storms. The monitored site allowed testing different snow fence designs under close to identical conditions over four winter seasons. The study also discusses the detailed monitoring system and analysis of weather forecast and meteorological conditions at the monitored sites. A main goal of the present study was to assess the performance of lightweight plastic snow fences with a lower porosity than the typical 50% porosity used in standard designs of such fences. The field data collected during the first winter was used to identify the best design for snow fences with a porosity of 50%. Flow fields obtained from numerical simulations showed that the fence design that worked the best during the first winter induced the formation of an elongated area of small velocity magnitude close to the ground. This information was used to identify other candidates for optimum design of fences with a lower porosity. Two of the designs with a fence porosity of 30% that were found to perform well based on results of numerical simulations were tested in the field during the second winter along with the best performing design for fences with a porosity of 50%. Field data showed that the length of the snow deposit away from the fence was reduced by about 30% for the two proposed lower-porosity (30%) fence designs compared to the best design identified for fences with a porosity of 50%. Moreover, one of the lower-porosity designs tested in the field showed no significant snow deposition within the bottom gap region beneath the fence. Thus, a major outcome of this study is to recommend using plastic snow fences with a porosity of 30%. It is expected that this lower-porosity design will continue to work well for even more severe snow events or for successive snow events occurring during the same winter. The approach advocated in the present study allowed making general recommendations for optimizing the design of lower-porosity plastic snow fences. This approach can be extended to improve the design of other types of snow fences. Some preliminary work for living snow fences is also discussed. Another major contribution of this study is to propose, develop protocols and test a novel technique based on close range photogrammetry (CRP) to quantify the snow deposits trapped snow fences. As image data can be acquired continuously, the time evolution of the volume of snow retained by a snow fence during a storm or during a whole winter season can, in principle, be obtained. Moreover, CRP is a non-intrusive method that eliminates the need to perform man-made measurements during the storms, which are difficult and sometimes dangerous to perform. Presently, there is lots of empiricism in the design of snow fences due to lack of data on fence storage capacity on how snow deposits change with the fence design and snow storm characteristics and in the estimation of the main parameters used by the state DOTs to design snow fences at a given site. The availability of such information from CRP measurements should provide critical data for the evaluation of the performance of a certain snow fence design that is tested by the IDOT. As part of the present study, the novel CRP method is tested at several sites. The present study also discusses some attempts and preliminary work to determine the snow relocation coefficient which is one of the main variables that has to be estimated by IDOT engineers when using the standard snow fence design software (Snow Drift Profiler, Tabler, 2006). Our analysis showed that standard empirical formulas did not produce reasonable values when applied at the Iowa test sites monitored as part of the present study and that simple methods to estimate this variable are not reliable. The present study makes recommendations for the development of a new methodology based on Large Scale Particle Image Velocimetry that can directly measure the snow drift fluxes and the amount of snow relocated by the fence.

On the Selection of Non-Invasive Methods Based on Speech Analysis Oriented to Automatic Alzheimer Disease Diagnosis

The work presented here is part of a larger study to identify novel technologies and biomarkers for early Alzheimer disease (AD) detection and it focuses on evaluating the suitability of a new approach for early AD diagnosis by non-invasive methods. The purpose is to examine in a pilot study the potential of applying intelligent algorithms to speech features obtained from suspected patients in order to contribute to the improvement of diagnosis of AD and its degree of severity. In this sense, Artificial Neural Networks (ANN) have been used for the automatic classification of the two classes (AD and control subjects). Two human issues have been analyzed for feature selection: Spontaneous Speech and Emotional Response. Not only linear features but also non-linear ones, such as Fractal Dimension, have been explored. The approach is non invasive, low cost and without any side effects. Obtained experimental results were very satisfactory and promising for early diagnosis and classification of AD patients.

Structure-function analysis of the human TFIIB-related factor II protein reveals an essential role for the C-terminal domain in RNA polymerase III transcription.

The transcription factors TFIIB, Brf1, and Brf2 share related N-terminal zinc ribbon and core domains. TFIIB bridges RNA polymerase II (Pol II) with the promoter-bound preinitiation complex, whereas Brf1 and Brf2 are involved, as part of activities also containing TBP and Bdp1 and referred to here as Brf1-TFIIIB and Brf2-TFIIIB, in the recruitment of Pol III. Brf1-TFIIIB recruits Pol III to type 1 and 2 promoters and Brf2-TFIIIB to type 3 promoters such as the human U6 promoter. Brf1 and Brf2 both have a C-terminal extension absent in TFIIB, but their C-terminal extensions are unrelated. In yeast Brf1, the C-terminal extension interacts with the TBP/TATA box complex and contributes to the recruitment of Bdp1. Here we have tested truncated Brf2, as well as Brf2/TFIIB chimeric proteins for U6 transcription and for assembly of U6 preinitiation complexes. Our results characterize functions of various human Brf2 domains and reveal that the C-terminal domain is required for efficient association of the protein with U6 promoter-bound TBP and SNAP(c), a type 3 promoter-specific transcription factor, and for efficient recruitment of Bdp1. This in turn suggests that the C-terminal extensions in Brf1 and Brf2 are crucial to specific recruitment of Pol III over Pol II.

On Automatic Diagnosis of Alzheimer's Disease based on Spontaneous Speech Analysis and Emotional Temperature

Alzheimer's disease is the most prevalent form of progressive degenerative dementia; it has a high socio-economic impact in Western countries. Therefore it is one of the most active research areas today. Alzheimer's is sometimes diagnosed by excluding other dementias, and definitive confirmation is only obtained through a post-mortem study of the brain tissue of the patient. The work presented here is part of a larger study that aims to identify novel technologies and biomarkers for early Alzheimer's disease detection, and it focuses on evaluating the suitability of a new approach for early diagnosis of Alzheimer’s disease by non-invasive methods. The purpose is to examine, in a pilot study, the potential of applying Machine Learning algorithms to speech features obtained from suspected Alzheimer sufferers in order help diagnose this disease and determine its degree of severity. Two human capabilities relevant in communication have been analyzed for feature selection: Spontaneous Speech and Emotional Response. The experimental results obtained were very satisfactory and promising for the early diagnosis and classification of Alzheimer’s disease patients.

Thermoset Composite Concrete Reinforcement, HR-325, Part 2, 1992

This is the second part of the final report submitted to the Iowa Department of Transportation. Part 1 contained a comparison of unaged fiber composite and steel dowels and derivation of the appropriate theoretical model for analyzing the results. Part 2 of this final report covers the theoretical and experimental models for accelerated aging of fiber composite reinforcing bars and dowels cast in a concrete environment. Part 2 contains results from testing of unaged and aged fiber composite dowels and steel dowels, in addition to unaged and aged fiber composite reinforcing bars. Additional tests have been performed on unaged dowels (both steel and fibercomposite) to verify results from Part 1 and to keep the testing program consistent. Slight modifications have been made to the dowel specimens presented in Part 1. These modifications are noted in the Section 3.4 of this report. The flexural modulus of elasticity for the FC dowel bar given in Part 1 of the final report (Table 3. 2) was for the incorrect structural shape (non-circular cross section). The value is corrected and given in Part 2 of the final report (Table 3.4 for the.modulus of elasticity supplied by the manufacturer, and Tables 3. 5 and 3. 6 for experimentally determined modulus of elasticities) • The value in Part 1 was not used for any analysis of the FC dowel bars.

The Use of Remote Sensing Techniques Compared to Traditional Archaeological Phase II Testing Methods: A Cost-Benefit Analysis, HR-524, 1986

Remote sensing was utilized in the Phase II Cultural Resources Investigation for this project in lieu of extensive excavations. The purpose of the present report is to compare the costs and benefits of the use of remote sensing to the hypothetical use of traditional excavation methods for this project. Estimates for this hypothetical situation are based on the project archaeologist's considerable past experience in conducting similar investigations. Only that part of the Phase II investigation involving field investigations is addressed in this report. Costs for literature review, laboratory analysis, report preparation, etc., are not included. The project manager proposed the use of this technique for the fol lowing logistic, safety and budgetary reasons.

New perspectives in the use of ink evidence in forensic science: Part III: Operational applications and evaluation.

The research reported in this series of article aimed at (1) automating the search of questioned ink specimens in ink reference collections and (2) at evaluating the strength of ink evidence in a transparent and balanced manner. These aims require that ink samples are analysed in an accurate and reproducible way and that they are compared in an objective and automated way. This latter requirement is due to the large number of comparisons that are necessary in both scenarios. A research programme was designed to (a) develop a standard methodology for analysing ink samples in a reproducible way, (b) comparing automatically and objectively ink samples and (c) evaluate the proposed methodology in forensic contexts. This report focuses on the last of the three stages of the research programme. The calibration and acquisition process and the mathematical comparison algorithms were described in previous papers [C. Neumann, P. Margot, New perspectives in the use of ink evidence in forensic science-Part I: Development of a quality assurance process for forensic ink analysis by HPTLC, Forensic Sci. Int. 185 (2009) 29-37; C. Neumann, P. Margot, New perspectives in the use of ink evidence in forensic science-Part II: Development and testing of mathematical algorithms for the automatic comparison of ink samples analysed by HPTLC, Forensic Sci. Int. 185 (2009) 38-50]. In this paper, the benefits and challenges of the proposed concepts are tested in two forensic contexts: (1) ink identification and (2) ink evidential value assessment. The results show that different algorithms are better suited for different tasks. This research shows that it is possible to build digital ink libraries using the most commonly used ink analytical technique, i.e. high-performance thin layer chromatography, despite its reputation of lacking reproducibility. More importantly, it is possible to assign evidential value to ink evidence in a transparent way using a probabilistic model. It is therefore possible to move away from the traditional subjective approach, which is entirely based on experts' opinion, and which is usually not very informative. While there is room for the improvement, this report demonstrates the significant gains obtained over the traditional subjective approach for the search of ink specimens in ink databases, and the interpretation of their evidential value.

Simulation and Analysis of Arterial Traffic Operations Along the U.S. 61 Corridor in Burlington, Iowa, 1998

The Center for Transportation Research and Education (CTRE) used the traffic simulation model CORSIM to access proposed capacity and safety improvement strategies for the U.S. 61 corridor through Burlington, Iowa. The comparison between the base and alternative models allow for evaluation of the traffic flow performance under the existing conditions as well as other design scenarios. The models also provide visualization of performance for interpretation by technical staff, public policy makers, and the public. The objectives of this project are to evaluate the use of traffic simulation models for future use by the Iowa Department of Transportation (DOT) and to develop procedures for employing simulation modeling to conduct the analysis of alternative designs. This report presents both the findings of the U.S. 61 evaluation and an overview of model development procedures. The first part of the report includes the simulation modeling development procedures. The simulation analysis is illustrated through the Burlington U.S. 61 corridor case study application. Part I is not intended to be a user manual but simply introductory guidelines for traffic simulation modeling. Part II of the report evaluates the proposed improvement concepts in a side by side comparison of the base and alternative models.

Rural Expressway Intersection Synthesis of Practice and Crash Analysis, 2004

This report presents a national synthesis of rural expressway, two-way stop -controlled (TWSC) intersection safety strategies and intersection designs and an analysis of Iowa expressway TWSC intersection crash characteristics. A rural expressway is a multi-lane highway with a divided median and with mostly at -grade intersections, although some intersections may be grade separated. The synthesis of intersection strategies is conducted in two parts. The first is a literature review and the second part is a national survey of strategies currently being applied by state transportation agencies. The characterization of crash patterns at TWSC expressway intersections is examined through the analysis of 5 years of crash data at 644 intersections.

Consolidation with Radioimmunotherapy May Prolong Survival in First Remission of Mantle Cell Lymphoma Patients Uneligible for Stem Cell Transplantation, An Analysis of the International RIT-Network

Background: Mantle cell lymphoma (MCL) is a rare subtype (3-9%) of Non Hodgkin Lymphoma (NHL) with a relatively poor prognosis (5-year survival < 40%). Although consolidation of first remission with autologous stem cell transplantation (ASCT) is regarded as "golden standard", less than half of the patients may be subjected to this intensive treatment due to advanced age and co-morbidities. Standard-dose non-myeloablative radioimmunotherapy (RIT) seems to be a very efficient approach for treatment of certain NHL. However, there are almost no data available on the efficacy and safety of RIT in MCL. Methods and Patients: In the RIT-Network, a web-based international registry collecting real observational data from RIT-treated patients, 115 MCL patients treated with ibritumomab tiuxetan were recorded. Most of the patients were elderly males with advanced stage of the disease: median age - 63 (range 31-78); males - 70.4%, stage III/IV - 92%. RIT (i.e. application of ibritumomab tiuxetan) was a part of the first line therapy in 48 pts. (43%). Further 38 pts. (33%) received ibritumomab tiuxetan after two previous chemotherapy regimens, and 33 pts. (24%) after completing 3-8 lines. In 75 cases RIT was applied as a consolidation of chemotherapy induced response; the rest of the patients received ibritumomab tiuxetan because of relapse/refractory disease. At the moment follow up data are available for 74 MCL patients. Results: After RIT the patients achieved high response rate: CR 60.8%, PR 25.7%, and SD 2.7%. Only 10.8% of the patients progressed. For survival analysis many data had to be censored since the documentation had not been completed yet. The projected 3-year overall survival (OAS, fig.1 - image 001.gif) after radioimmunotherapy was 72% for pts. subjected to RIT consolidation versus 29% for those treated in relapse/refractory disease (p=0.03). RIT was feasible for almost all patients; only 3 procedure-related deaths were reported in the whole group. The main adverse event was hematological toxicity (grade III/IV cytopenias) showing a median time of recovery of Hb, WBC and Plt of 45, 40 and 38 days respectively. Conclusion: Standard-dose non-myeloablative RIT is a feasible and safe treatment modality, even for elderly MCL pts. Consolidation radioimmunotherapy with ibritumomab tiuxetan may prolong survival of patients who achieved clinical response after chemotherapy. Therefore, this consolidation approach should be considered as a treatment strategy for those, who are not eligible for ASCT. RIT also has a potential role as a palliation therapy in relapsing/resistant cases.

A Continuous Span Aluminum Girder Concrete Deck Bridge - Part 1 of 2: Field Test Performance and Evaluation, 1996

This report addresses the field testing and analysis of those results to establish the behavior of the original Clive Road Bridge that carried highway traffic over Interstate 80 (I-80) in the northwest region of Des Moines, Iowa. The bridge was load tested in 1959, shortly after its construction and in 1993, just prior to its demolition. This report presents some of the results from both field tests, finite element predictions of the behavior of aluminum bridge girders, and load distribution studies.

Meta-analysis : subclinical thyroid dysfunction and the risk for coronary heart disease and mortality

Rapport de synthèse : Description : ce travail de thèse évalue de façon systématique les études sur l'association entre les dysfonctions thyroïdiennes infracliniques d'une part, et la maladie coronarienne et la mortalité d'autre part. Les hypothyroïdies infracliniques affectent environ 4-5% de la population adulte alors que la prévalence de l'hyperthyroïdie infraclinique est inférieure (environ 1%). L'éventuelle association entre elles pourrait justifier un dépistage systématique des dysfonctions thyroïdiennes infracliniques. Les précédentes études sur l'association entre l'hypothyroïdie infraclinique et la maladie coronarienne ont donné des résultats conflictuels. La parution de nouveaux articles récents basés sur de grandes cohortes prospectives nous a permis d'effectuer une méta-analyse basée uniquement sur des études de cohorte prospectives, augmentant ainsi la validité des résultats. Résultats: 10 des 12 études identifiées pour notre revue systématique sont basées sur des cohortes issues de la population générale («population-based »), regroupant en tout 14 449 participants. Ces 10 études examinent toutes le risque associé à l'hypothyroïdie infraclinique (avec 2134 événements coronariens et 2822 décès), alors que 5 étudient également le risque associé à l'hyperthyroïdie infraclinique (avec 1392 événements coronariens et 1993 décès). En utilisant un modèle statistique de type random-effect model, le risque relatif [RR] lié à l'hypothyroïdie infraclinique pour la maladie coronarienne est de 1.20 (intervalle de confiance [IC] de 95%, 0.97 à 1.49). Le risque diminue lorsque l'on regroupe uniquement les études de meilleure qualité (RR compris entre 1.02 et 1.08). Il est plus élevé parmi les participants de moins de 65 ans (RR, 1.51 [IC, 1.09 à 2.09] et 1.05 [IC, 0.90 à 1.22] pour les études dont l'âge moyen des participants est >_ 65 ans). Le RR de la mortalité cardiovasculaire est de 1.18 (IC, 0.98 à 1.42) et de 1.12 (IC, 0.99 à 1.26) pour la mortalité totale. En cas d'hyperthyroïdie infraclinique, les RR de la maladie coronarienne sont de 1.21 (IC, 0.88 à 1.68), de 1.19 (IC, 0.81 à 1.76) pour la mortalité cardiovasculaire, et de 1.12 (IC, 0.89 à 1.42) pour la mortalité totale. Conclusions et perspectives : nos résultats montrent que les dysfonctions thyroïdiennes infracliniques (hypothyroïdie et hyperthyroïdie infracliniques) représentent un facteur de risque modifiable, bien que modéré, de la maladie coronarienne et de la mortalité. L'efficacité du traitement de ces dysfonctions thyroïdiennes infracliniques doit encore être prouvée du point de vue cardiovasculaire et de la mortalité. Il est nécessaire d'effectuer des études contrôlées contre placebo avec le risque cardiovasculaire et la mortalité comme critères d'efficacité, avant de pouvoir proposer des recommandations sur le dépistage des ces dysfonctions thyroïdiennes dans la population adulte.

Factors predisposing to dislocation after primary total hip arthroplasty: a multivariate analysis.

We conducted this study to determine the relative influence of various mechanical and patient-related factors on the incidence of dislocation after primary total hip asthroplasty (THA). Of 2,023 THAs, 21 patients who had at least 1 dislocation were compared with a control group of 21 patients without dislocation, matched for age, gender, pathology, and year of surgery. Implant positioning, seniority of the surgeon, American Society of Anesthesiologists (ASA) score, and diminished motor coordination were recorded. Data analysis included univariate and multivariate methods. The dislocation risk was 6.9 times higher if total anteversion was not between 40 degrees and 60 degrees and 10 times higher in patients with high ASA scores. Surgeons should pay attention to total anteversion (cup and stem) of THA. The ASA score should be part of the preoperative assessment of the dislocation risk.