Multiple Testing With an Empirical Alternative Hypothesis

An optimal multiple testing procedure is identified for linear hypotheses under the general linear model, maximizing the expected number of false null hypotheses rejected at any significance level. The optimal procedure depends on the unknown data-generating distribution, but can be consistently estimated. Drawing information together across many hypotheses, the estimated optimal procedure provides an empirical alternative hypothesis by adapting to underlying patterns of departure from the null. Proposed multiple testing procedures based on the empirical alternative are evaluated through simulations and an application to gene expression microarray data. Compared to a standard multiple testing procedure, it is not unusual for use of an empirical alternative hypothesis to increase by 50% or more the number of true positives identified at a given significance level.

A NOVEL AND SIMPLE RULE OF THUMB FOR MULTIPLICITY CONTROL IN EQUIVALENCE TESTING USING TWO ONE-SIDED TESTS

Equivalence testing is growing in use in scientific research outside of its traditional role in the drug approval process. Largely due to its ease of use and recommendation from the United States Food and Drug Administration guidance, the most common statistical method for testing (bio)equivalence is the two one-sided tests procedure (TOST). Like classical point-null hypothesis testing, TOST is subject to multiplicity concerns as more comparisons are made. In this manuscript, a condition that bounds the family-wise error rate (FWER) using TOST is given. This condition then leads to a simple solution for controlling the FWER. Specifically, we demonstrate that if all pairwise comparisons of k independent groups are being evaluated for equivalence, then simply scaling the nominal Type I error rate down by (k - 1) is sufficient to maintain the family-wise error rate at the desired value or less. The resulting rule is much less conservative than the equally simple Bonferroni correction. An example of equivalence testing in a non drug-development setting is given.

Testing Wisconsin asphalt mixtures for the 2002 AASHTO mechanistic design procedure

There has been a continuous evolutionary process in asphalt pavement design. In the beginning it was crude and based on past experience. Through research, empirical methods were developed based on materials response to specific loading at the AASHO Road Test. Today, pavement design has progressed to a mechanistic-empirical method. This methodology takes into account the mechanical properties of the individual layers and uses empirical relationships to relate them to performance. The mechanical tests that are used as part of this methodology include dynamic modulus and flow number, which have been shown to correlate with field pavement performance. This thesis was based on a portion of a research project being conducted at Michigan Technological University (MTU) for the Wisconsin Department of Transportation (WisDOT). The global scope of this project dealt with the development of a library of values as they pertain to the mechanical properties of the asphalt pavement mixtures paved in Wisconsin. Additionally, a comparison with the current associated pavement design to that of the new AASHTO Design Guide was conducted. This thesis describes the development of the current pavement design methodology as well as the associated tests as part of a literature review. This report also details the materials that were sampled from field operations around the state of Wisconsin and their testing preparation and procedures. Testing was conducted on available round robin and three Wisconsin mixtures and the main results of the research were: The test history of the Superpave SPT (fatigue and permanent deformation dynamic modulus) does not affect the mean response for both dynamic modulus and flow number, but does increase the variability in the test results of the flow number. The method of specimen preparation, compacting to test geometry versus sawing/coring to test geometry, does not statistically appear to affect the intermediate and high temperature dynamic modulus and flow number test results. The 2002 AASHTO Design Guide simulations support the findings of the statistical analyses that the method of specimen preparation did not impact the performance of the HMA as a structural layer as predicted by the Design Guide software. The methodologies for determining the temperature-viscosity relationship as stipulated by Witczak are sensitive to the viscosity test temperatures employed. The increase in asphalt binder content by 0.3% was found to actually increase the dynamic modulus at the intermediate and high test temperature as well as flow number. This result was based the testing that was conducted and was contradictory to previous research and the hypothesis that was put forth for this thesis. This result should be used with caution and requires further review. Based on the limited results presented herein, the asphalt binder grade appears to have a greater impact on performance in the Superpave SPT than aggregate angularity. Dynamic modulus and flow number was shown to increase with traffic level (requiring an increase in aggregate angularity) and with a decrease in air voids and confirm the hypotheses regarding these two factors. Accumulated micro-strain at flow number as opposed to the use of flow number appeared to be a promising measure for comparing the quality of specimens within a specific mixture. At the current time the Design Guide and its associate software needs to be further improved prior to implementation by owner/agencies.

STATISTICAL METHODS FOR RARE AND COMMON VARIANT ASSOCIATION STUDIES

Complex human diseases are a major challenge for biological research. The goal of my research is to develop effective methods for biostatistics in order to create more opportunities for the prevention and cure of human diseases. This dissertation proposes statistical technologies that have the ability of being adapted to sequencing data in family-based designs, and that account for joint effects as well as gene-gene and gene-environment interactions in the GWA studies. The framework includes statistical methods for rare and common variant association studies. Although next-generation DNA sequencing technologies have made rare variant association studies feasible, the development of powerful statistical methods for rare variant association studies is still underway. Chapter 2 demonstrates two adaptive weighting methods for rare variant association studies based on family data for quantitative traits. The results show that both proposed methods are robust to population stratification, robust to the direction and magnitude of the effects of causal variants, and more powerful than the methods using weights suggested by Madsen and Browning [2009]. In Chapter 3, I extended the previously proposed test for Testing the effect of an Optimally Weighted combination of variants (TOW) [Sha et al., 2012] for unrelated individuals to TOW &ndash F, TOW for Family &ndash based design. Simulation results show that TOW &ndash F can control for population stratification in wide range of population structures including spatially structured populations, is robust to the directions of effect of causal variants, and is relatively robust to percentage of neutral variants. In GWA studies, this dissertation consists of a two &ndash locus joint effect analysis and a two-stage approach accounting for gene &ndash gene and gene &ndash environment interaction. Chapter 4 proposes a novel two &ndash stage approach, which is promising to identify joint effects, especially for monotonic models. The proposed approach outperforms a single &ndash marker method and a regular two &ndash stage analysis based on the two &ndash locus genotypic test. In Chapter 5, I proposed a gene &ndash based two &ndash stage approach to identify gene &ndash gene and gene &ndash environment interactions in GWA studies which can include rare variants. The two &ndash stage approach is applied to the GAW 17 dataset to identify the interaction between KDR gene and smoking status.

Testing an alternative search algorithm for compound identification with the 'Wiley Registry of Tandem Mass Spectral Data. MSforID'

A tandem mass spectral database system consists of a library of reference spectra and a search program. State-of-the-art search programs show a high tolerance for variability in compound-specific fragmentation patterns produced by collision-induced decomposition and enable sensitive and specific 'identity search'. In this communication, performance characteristics of two search algorithms combined with the 'Wiley Registry of Tandem Mass Spectral Data, MSforID' (Wiley Registry MSMS, John Wiley and Sons, Hoboken, NJ, USA) were evaluated. The search algorithms tested were the MSMS search algorithm implemented in the NIST MS Search program 2.0g (NIST, Gaithersburg, MD, USA) and the MSforID algorithm (John Wiley and Sons, Hoboken, NJ, USA). Sample spectra were acquired on different instruments and, thus, covered a broad range of possible experimental conditions or were generated in silico. For each algorithm, more than 30,000 matches were performed. Statistical evaluation of the library search results revealed that principally both search algorithms can be combined with the Wiley Registry MSMS to create a reliable identification tool. It appears, however, that a higher degree of spectral similarity is necessary to obtain a correct match with the NIST MS Search program. This characteristic of the NIST MS Search program has a positive effect on specificity as it helps to avoid false positive matches (type I errors), but reduces sensitivity. Thus, particularly with sample spectra acquired on instruments differing in their Setup from tandem-in-space type fragmentation, a comparably higher number of false negative matches (type II errors) were observed by searching the Wiley Registry MSMS.

Beyond statistical learning? Continuous sequence repetition matters in implicit sequence learning

Typically, statistical learning is investigated by testing the acquisition of specific items or forming general rules. As implicit sequence learning also involves the extraction of regularities from the environment, it can also be considered as an instance of statistical learning. In the present study, a Serial Reaction Time Task was used to test whether the continuous versus interleaved repetition of a sequence affects implicit learning despite the equal exposure to the sequences. The results revealed a sequence learning advantage for the continuous repetition condition compared to the interleaved condition. This suggests that by repetition, additional sequence information was extracted although the exposure to the sequences was identical as in the interleaved condition. The results are discussed in terms of similarities and potential differences between typical statistical learning paradigms and sequence learning.

Statistical Methods for Differential Expressions of Genes Detected in Multiple-Condition Experiment of Microarray

Most studies of differential gene-expressions have been conducted between two given conditions. The two-condition experimental (TCE) approach is simple in that all genes detected display a common differential expression pattern responsive to a common two-condition difference. Therefore, the genes that are differentially expressed under the other conditions other than the given two conditions are undetectable with the TCE approach. In order to address the problem, we propose a new approach called multiple-condition experiment (MCE) without replication and develop corresponding statistical methods including inference of pairs of conditions for genes, new t-statistics, and a generalized multiple-testing method for any multiple-testing procedure via a control parameter C. We applied these statistical methods to analyze our real MCE data from breast cancer cell lines and found that 85 percent of gene-expression variations were caused by genotypic effects and genotype-ANAX1 overexpression interactions, which agrees well with our expected results. We also applied our methods to the adenoma dataset of Notterman et al. and identified 93 differentially expressed genes that could not be found in TCE. The MCE approach is a conceptual breakthrough in many aspects: (a) many conditions of interests can be conducted simultaneously; (b) study of association between differential expressions of genes and conditions becomes easy; (c) it can provide more precise information for molecular classification and diagnosis of tumors; (d) it can save lot of experimental resources and time for investigators.^

Uniformly reweighted belief propagation for distributed Bayesian hypothesis testing

Belief propagation (BP) is a technique for distributed inference in wireless networks and is often used even when the underlying graphical model contains cycles. In this paper, we propose a uniformly reweighted BP scheme that reduces the impact of cycles by weighting messages by a constant ?edge appearance probability? rho ? 1. We apply this algorithm to distributed binary hypothesis testing problems (e.g., distributed detection) in wireless networks with Markov random field models. We demonstrate that in the considered setting the proposed method outperforms standard BP, while maintaining similar complexity. We then show that the optimal ? can be approximated as a simple function of the average node degree, and can hence be computed in a distributed fashion through a consensus algorithm.

REST service testing based on inferred XML schemas

The concept of service oriented architecture has been extensively explored in software engineering, due to the fact that it produces architectures made up of several interconnected modules, easy to reuse when building new systems. This approach to design would be impossible without interconnection mechanisms such as REST (Representationa State Transfer) services, which allow module communication while minimizing coupling. . However, this low coupling brings disadvantages, such as the lack of transparency, which makes it difficult to sistematically create tests without knowledge of the inner working of a system. In this article, we present an automatic error detection system for REST services, based on a statistical analysis over responses produced at multiple service invocations. Thus, a service can be systematically tested without knowing its full specification. The method can find errors in REST services which could not be identified by means of traditional testing methods, and provides limited testing coverage for services whose response format is unknown. It can be also useful as a complement to other testing mechanisms.

Experimental and statistical investigation of canonical problems in sloshing

En hidrodinámica, el fenómeno de Sloshing se puede definir como el movimiento de la superficie libre de un fluido dentro de un contenedor sometido a fuerzas y perturbaciones externas. El fluido en cuestión experimenta violentos movimientos con importantes deformaciones de su superficie libre. La dinámica del fluido puede llegar a generar cargas hidrodinámicas considerables las cuales pueden afectar la integridad estructural y/o comprometer la estabilidad del vehículo que transporta dicho contenedor. El fenómeno de Sloshing ha sido extensivamente investigado matemática, numérica y experimentalmente, siendo el enfoque experimental el más usado debido a la complejidad del problema, para el cual los modelos matemáticos y de simulación son aun incapaces de predecir con suficiente rapidez y precisión las cargas debidas a dicho fenómeno. El flujo generado por el Sloshing usualmente se caracteriza por la presencia de un fluido multifase (gas-liquido) y turbulencia. Reducir al máximo posible la complejidad del fenómeno de Sloshing sin perder la esencia del problema es el principal reto de esta tesis doctoral, donde un trabajo experimental enfocado en casos canónicos de Sloshing es presentado y documentado con el objetivo de aumentar la comprensión de dicho fenómeno y por tanto intentar proveer información valiosa para validaciones de códigos numéricos. El fenómeno de Sloshing juega un papel importante en la industria del transporte marítimo de gas licuado (LNG). El mercado de LNG en los últimos años ha reportado un crecimiento hasta tres veces mayor al de los mercados de petróleo y gas convencionales. Ingenieros en laboratorios de investigación e ingenieros adscritos a la industria del LNG trabajan continuamente buscando soluciones económicas y seguras para contener, transferir y transportar grandes volúmenes de LNG. Los buques transportadores de LNG (LNGC) han pasado de ser unos pocos buques con capacidad de 75000 m3 hace unos treinta años, a una amplia flota con una capacidad de 140000 m3 actualmente. En creciente número, hoy día se construyen buques con capacidades que oscilan entre 175000 m3 y 250000 m3. Recientemente un nuevo concepto de buque LNG ha salido al mercado y se le conoce como FLNG. Un FLNG es un buque de gran valor añadido que solventa los problemas de extracción, licuefacción y almacenamiento del LNG, ya que cuenta con equipos de extracción y licuefacción a bordo, eliminando por tanto las tareas de transvase de las estaciones de licuefacción en tierra hacia los buques LNGC. EL LNG por tanto puede ser transferido directamente desde el FLNG hacia los buques LNGC en mar abierto. Niveles de llenado intermedios en combinación con oleaje durante las operaciones de trasvase inducen movimientos en los buques que generan por tanto el fenómeno de Sloshing dentro de los tanques de los FLNG y los LNGC. El trabajo de esta tesis doctoral lidia con algunos de los problemas del Sloshing desde un punto de vista experimental y estadístico, para ello una serie de tareas, descritas a continuación, se han llevado a cabo : 1. Un dispositivo experimental de Sloshing ha sido configurado. Dicho dispositivo ha permitido ensayar secciones rectangulares de tanques LNGC a escala con movimientos angulares de un grado de libertad. El dispositivo experimental ha sido instrumentado para realizar mediciones de movimiento, presiones, vibraciones y temperatura, así como la grabación de imágenes y videos. 2. Los impactos de olas generadas dentro de una sección rectangular de un LNGC sujeto a movimientos regulares forzados han sido estudiados mediante la caracterización del fenómeno desde un punto de vista estadístico enfocado en la repetitividad y la ergodicidad del problema. 3. El estudio de los impactos provocados por movimientos regulares ha sido extendido a un escenario más realístico mediante el uso de movimientos irregulares forzados. 4. El acoplamiento del Sloshing generado por el fluido en movimiento dentro del tanque LNGC y la disipación de la energía mecánica de un sistema no forzado de un grado de libertad (movimiento angular) sujeto a una excitación externa ha sido investigado. 5. En la última sección de esta tesis doctoral, la interacción entre el Sloshing generado dentro en una sección rectangular de un tanque LNGC sujeto a una excitación regular y un cuerpo elástico solidario al tanque ha sido estudiado. Dicho estudio corresponde a un problema de interacción fluido-estructura. Abstract In hydrodynamics, we refer to sloshing as the motion of liquids in containers subjected to external forces with large free-surface deformations. The liquid motion dynamics can generate loads which may affect the structural integrity of the container and the stability of the vehicle that carries such container. The prediction of these dynamic loads is a major challenge for engineers around the world working on the design of both the container and the vehicle. The sloshing phenomenon has been extensively investigated mathematically, numerically and experimentally. The latter has been the most fruitful so far, due to the complexity of the problem, for which the numerical and mathematical models are still incapable of accurately predicting the sloshing loads. The sloshing flows are usually characterised by the presence of multiphase interaction and turbulence. Reducing as much as possible the complexity of the sloshing problem without losing its essence is the main challenge of this phd thesis, where experimental work on selected canonical cases are presented and documented in order to better understand the phenomenon and to serve, in some cases, as an useful information for numerical validations. Liquid sloshing plays a key roll in the liquified natural gas (LNG) maritime transportation. The LNG market growth is more than three times the rated growth of the oil and traditional gas markets. Engineers working in research laboratories and companies are continuously looking for efficient and safe ways for containing, transferring and transporting the liquified gas. LNG carrying vessels (LNGC) have evolved from a few 75000 m3 vessels thirty years ago to a huge fleet of ships with a capacity of 140000 m3 nowadays and increasing number of 175000 m3 and 250000 m3 units. The concept of FLNG (Floating Liquified Natural Gas) has appeared recently. A FLNG unit is a high value-added vessel which can solve the problems of production, treatment, liquefaction and storage of the LNG because the vessel is equipped with a extraction and liquefaction facility. The LNG is transferred from the FLNG to the LNGC in open sea. The combination of partial fillings and wave induced motions may generate sloshing flows inside both the LNGC and the FLNG tanks. This work has dealt with sloshing problems from a experimental and statistical point of view. A series of tasks have been carried out: 1. A sloshing rig has been set up. It allows for testing tanks with one degree of freedom angular motion. The rig has been instrumented to measure motions, pressure and conduct video and image recording. 2. Regular motion impacts inside a rectangular section LNGC tank model have been studied, with forced motion tests, in order to characterise the phenomenon from a statistical point of view by assessing the repeatability and practical ergodicity of the problem. 3. The regular motion analysis has been extended to an irregular motion framework in order to reproduce more realistic scenarios. 4. The coupled motion of a single degree of freedom angular motion system excited by an external moment and affected by the fluid moment and the mechanical energy dissipation induced by sloshing inside the tank has been investigated. 5. The last task of the thesis has been to conduct an experimental investigation focused on the strong interaction between a sloshing flow in a rectangular section of a LNGC tank subjected to regular excitation and an elastic body clamped to the tank. It is thus a fluid structure interaction problem.

Development and psychometric testing of the clinical learning environment, supervision and nurse teacher evaluation scale (CLES+T): The Spanish version

Background: The Clinical Learning Environment, Supervision and Nurse Teacher scale is a reliable and valid instrument to evaluate the quality of the clinical learning process in international nursing education contexts. Objectives: This paper reports the development and psychometric testing of the Spanish version of the Clinical Learning Environment, Supervision and Nurse Teacher scale. Design: Cross-sectional validation study of the scale. Setting: 10 public and private hospitals in the Alicante area, and the Faculty of Health Sciences (University of Alicante, Spain). Participants: 370 student nurses on clinical placement (January 2011–March 2012). Methods: The Clinical Learning Environment, Supervision and Nurse Teacher scale was translated using the modified direct translation method. Statistical analyses were performed using PASW Statistics 18 and AMOS 18.0.0 software. A multivariate analysis was conducted in order to assess construct validity. Cronbach’s alpha coefficient was used to evaluate instrument reliability. Results: An exploratory factorial analysis identified the five dimensions from the original version, and explained 66.4% of the variance. Confirmatory factor analysis supported the factor structure of the Spanish version of the instrument. Cronbach’s alpha coefficient for the scale was .95, ranging from .80 to .97 for the subscales. Conclusion: This version of the Clinical Learning Environment, Supervision and Nurse Teacher scale instrument showed acceptable psychometric properties for use as an assessment scale in Spanish-speaking countries.