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.

Accelerometer based measurements of combustion in an automotive turbocharged diesel engine

The capability to detect combustion in a diesel engine has the potential of being an important control feature to meet increasingly stringent emission regulations, develop alternative combustion strategies, and use of biofuels. In this dissertation, block mounted accelerometers were investigated as potential feedback sensors for detecting combustion characteristics in a high-speed, high pressure common rail (HPCR), 1.9L diesel engine. Accelerometers were positioned in multiple placements and orientations on the engine, and engine testing was conducted under motored, single and pilot-main injection conditions. Engine tests were conducted at varying injection timings, engine loads, and engine speeds to observe the resulting time and frequency domain changes of the cylinder pressure and accelerometer signals. The frequency content of the cylinder pressure based signals and the accelerometer signals between 0.5 kHz and 6 kHz indicated a strong correlation with coherence values of nearly 1. The accelerometers were used to produce estimated combustion signals using the Frequency Response Functions (FRF) measured from the frequency domain characteristics of the cylinder pressure signals and the response of the accelerometers attached to the engine block. When compared to the actual combustion signals, the estimated combustion signals produced from the accelerometer response had Root Mean Square Errors (RMSE) between 7% and 25% of the actual signals peak value. Weighting the FRF’s from multiple test conditions along their frequency axis with the coherent output power reduced the median RMSE of the estimated combustion signals and the 95th percentile of RMSE produced from each test condition. The RMSE’s of the magnitude based combustion metrics including peak cylinder pressure, MPG, peak ROHR, and work estimated from the combustion signals produced by the accelerometer responses were between 15% and 50% of their actual value. The MPG measured from the estimated pressure gradient shared a direct relationship to the actual MPG. The location based combustion metrics such as the location of peak values and burn durations were capable of RMSE measurements as low as 0.9°. Overall, accelerometer based combustion sensing system was capable of detecting combustion and providing feedback regarding the in cylinder combustion process

ANIMATED TRANSITION IN SIMILARITY-BASED TILED IMAGE LAYOUT

Effective techniques for organizing and visualizing large image collections are in growing demand as visual search gets increasingly popular. iMap is a treemap representation for visualizing and navigating image search and clustering results based on the evaluation of image similarity using both visual and textual information. iMap not only makes effective use of available display area to arrange images but also maintains stable update when images are inserted or removed during the query. A key challenge of using iMap lies in the difficult to follow and track the changes when updating the image arrangement as the query image changes. For many information visualization applications, showing the transition when interacting with the data is critically important as it can help users better perceive the changes and understand the underlying data. This work investigates the effectiveness of animated transition in a tiled image layout where the spiral arrangement of the images is based on their similarity. Three aspects of animated transition are considered, including animation steps, animation actions, and flying paths. Exploring and weighting the advantages and disadvantages of different methods for each aspect and in conjunction with the characteristics of the spiral image layout, we present an integrated solution, called AniMap, for animating the transition from an old layout to a new layout when a different image is selected as the query image. To smooth the animation and reduce the overlap among images during the transition, we explore different factors that might have an impact on the animation and propose our solution accordingly. We show the effectiveness of our animated transition solution by demonstrating experimental results and conducting a comparative user study.

[Complementary and alternative medicine in primary care in Switzerland]

OBJECTIVE: This study investigated the current supply of complementary and alternative medicine (CAM) in Swiss primary care. Information was collected on physicians' qualifications in CAM, frequency of patients' demand for CAM, physicians' supply and temporal resources for CAM as well as physicians' referrals to CAM. MATERIAL AND METHODS: 750 (500 German-speaking and 250 French-speaking) randomly selected Swiss female and male primary care physicians were asked to complete a questionnaire (response rate 50.4%). Sociodemographic data on professional training, place of residence, and sex were used to calculate a weighting factor to correct the responders' data in the analysis accordingly. RESULTS: 14.2% of the physicians were qualified in at least one CAM discipline. Around 30% (95% confidence interval 25.4-34.6%) of the physicians were asked for CAM by their patients more than once a week. Homeopathy and phytotherapy were the most frequently offered therapies, followed by traditional Chinese medicine (TCM)/acupuncture. 62.5% (57.6-67.4%) of the physicians refer their patients to CAM. Most patients were referred to TCM/acupuncture. Of the 37.2% (32.6-42.4%) of the physicians who do not refer their patients to CAM, around 40% (35.1-44.9%) offer it themselves. CONCLUSION: About three quarters of the physicians offer CAM themselves or refer their patients to CAM treatments. CAM is very important in primary medical care in Switzerland. Clear regulations for CAM are required in order to ensure a high quality in care.

Multimodal approach in the use of clinical scoring, morphological MRI and biochemical T2-mapping and diffusion-weighted imaging in their ability to assess differences between cartilage repair tissue after microfracture therapy and matrix-associated autologous chondrocyte transplantation: a pilot study

OBJECTIVE: The aim of the present pilot study is to show initial results of a multimodal approach using clinical scoring, morphological magnetic resonance imaging (MRI) and biochemical T2-relaxation and diffusion-weighted imaging (DWI) in their ability to assess differences between cartilage repair tissue after microfracture therapy (MFX) and matrix-associated autologous chondrocyte transplantation (MACT). METHOD: Twenty patients were cross-sectionally evaluated at different post-operative intervals from 12 to 63 months after MFX and 12-59 months after MACT. The two groups were matched by age (MFX: 36.0+/-10.4 years; MACT: 35.1+/-7.7 years) and post-operative interval (MFX: 32.6+/-16.7 months; MACT: 31.7+/-18.3 months). After clinical evaluation using the Lysholm score, 3T-MRI was performed obtaining the MR observation of cartilage repair tissue (MOCART) score as well as T2-mapping and DWI for multi-parametric MRI. Quantitative T2-relaxation was achieved using a multi-echo spin-echo sequence; semi-quantitative diffusion-quotient (signal intensity without diffusion-weighting divided by signal intensity with diffusion weighting) was prepared by a partially balanced, steady-state gradient-echo pulse sequence. RESULTS: No differences in Lysholm (P=0.420) or MOCART (P=0.209) score were observed between MFX and MACT. T2-mapping showed lower T2 values after MFX compared to MACT (P=0.039). DWI distinguished between healthy cartilage and cartilage repair tissue in both procedures (MFX: P=0.001; MACT: P=0.007). Correlations were found between the Lysholm and the MOCART score (Pearson: 0.484; P=0.031), between the Lysholm score and DWI (Pearson:-0.557; P=0.011) and a trend between the Lysholm score and T2 (Person: 0.304; P=0.193). CONCLUSION: Using T2-mapping and DWI, additional information could be gained compared to clinical scoring or morphological MRI. In combination clinical, MR-morphological and MR-biochemical parameters can be seen as a promising multimodal tool in the follow-up of cartilage repair.

Dual energy versus single energy MDCT: measurement of radiation dose using adult abdominal imaging protocols

RATIONALE AND OBJECTIVES: The aim of this study was to measure the radiation dose of dual-energy and single-energy multidetector computed tomographic (CT) imaging using adult liver, renal, and aortic imaging protocols. MATERIALS AND METHODS: Dual-energy CT (DECT) imaging was performed on a conventional 64-detector CT scanner using a software upgrade (Volume Dual Energy) at tube voltages of 140 and 80 kVp (with tube currents of 385 and 675 mA, respectively), with a 0.8-second gantry revolution time in axial mode. Parameters for single-energy CT (SECT) imaging were a tube voltage of 140 kVp, a tube current of 385 mA, a 0.5-second gantry revolution time, helical mode, and pitch of 1.375:1. The volume CT dose index (CTDI(vol)) value displayed on the console for each scan was recorded. Organ doses were measured using metal oxide semiconductor field-effect transistor technology. Effective dose was calculated as the sum of 20 organ doses multiplied by a weighting factor found in International Commission on Radiological Protection Publication 60. Radiation dose saving with virtual noncontrast imaging reconstruction was also determined. RESULTS: The CTDI(vol) values were 49.4 mGy for DECT imaging and 16.2 mGy for SECT imaging. Effective dose ranged from 22.5 to 36.4 mSv for DECT imaging and from 9.4 to 13.8 mSv for SECT imaging. Virtual noncontrast imaging reconstruction reduced the total effective dose of multiphase DECT imaging by 19% to 28%. CONCLUSION: Using the current Volume Dual Energy software, radiation doses with DECT imaging were higher than those with SECT imaging. Substantial radiation dose savings are possible with DECT imaging if virtual noncontrast imaging reconstruction replaces precontrast imaging.

CP-MLR Directed QSAR Studies on the Antimycobacterial Activity of Functionalised Alkenols - Topological Descriptors in Modeling the Activity

The antimycobacterial activity of nitro/ acetamido alkenol derivatives and chloro/ amino alkenol derivatives has been analyzed through combinatorial protocol in multiple linear regression (CP-MLR) using different topological descriptors obtained from Dragon software. Among the topological descriptor classes considered in the study, the activity is correlated with simple topological descriptors (TOPO) and more complex 2D autocorrelation descriptors (2DAUTO). In model building the descriptors from other classes, that is, empirical, constitutional, molecular walk counts, modified Burden eigenvalues and Galvez topological charge indices have made secondary contribution in association with TOPO and / or 2DAUTO classes. The structure-activity correlations obtained with the TOPO descriptors suggest that less branched and saturated structural templates would be better for the activity. For both the series of compounds, in 2DAUTO the activity has been correlated to the descriptors having mass, volume and/ or polarizability as weighting component. In these two series of compounds, however, the regression coefficients of the descriptors have opposite arithmetic signs with respect to one another. Outwardly these two series of compounds appear very similar. But in terms of activity they belong to different segments of descriptor-activity profiles. This difference in the activity of these two series of compounds may be mainly due to the spacing difference between the C1 (also C6) substituents and rest of the functional groups in them.

Topological Descriptors in Modeling the HIV Inhibitory Activity of 2-Aryl-3-pyridyl-thiazolidin-4-ones

The HIV-1 RT inhibitory activity of 2-(2,6-dihalophenyl)-3-(substituted pyridin-2-yl)-thiazolidin-4-ones has been analyzed with different topological descriptors obtained from DRAGON software. Here, simple topological descriptors (TOPO), Galvez topological charge indices (GVZ) and 2D autocorrelation descriptors (2DAUTO) have been found to yield good predictive models for the activity of these compounds. The correlations obtained from the TOPO class descriptors suggest that less extended or compact saturated structural templates would be better for the activity. The participating GVZ class descriptors suggest that they have same degree of influence on the activity. In 2DAUTO class, the large participation of descriptors of lags seven and three indicate the association of activity information with the seven and three centered structural fragments of these compounds. The physicochemical weighting components of these descriptors suggest homogeneous influence of mass, volume, electronegativity and/ or polarizability on the activity.

View-Dependent Extraction of Contours with Distance Transforms for Adaptive Polygonal for adaptive polygonal Mesh-Simplification

During decades Distance Transforms have proven to be useful for many image processing applications, and more recently, they have started to be used in computer graphics environments. The goal of this paper is to propose a new technique based on Distance Transforms for detecting mesh elements which are close to the objects' external contour (from a given point of view), and using this information for weighting the approximation error which will be tolerated during the mesh simplification process. The obtained results are evaluated in two ways: visually and using an objective metric that measures the geometrical difference between two polygonal meshes.

English in England

The intention of the present volume is to unite the research of a range of scholars who have been working on features of non-standard, vernacular English which show an areal distribution, i.e. which cluster geographically across the world. Features common to an area can be due to (i) shared dialect input, (ii) common but separate innovations after settlement, or (iii) area-internal diffusion from one variety to another and/or others. The relative weighting of these factors is an important topic in the book and is a key focus in the 17 chapters. The book is divided into two large blocks, the first one consisting of case studies (8 chapters) and the second with features complexes (9 chapters). The former look at major anglophone locations from an areal perspective while the latter examine linguistic categories and features with a view to determine whether these could be areally based or not.

Omega-3 poly-unsaturated fatty acids for the prevention of severe neutropenic enterocolitis in patients with acute myeloid leukemia

Neutropenic enterocolitis is a potentially fatal complication of myeloablative chemotherapy in patients with acute myeloid leukemia. Omega-3 polyunsaturated fatty acids (PUFA) are precursors of potent anti-inflammatory prostaglandins. Our aim was to explore the safety and effectiveness of omega-3 PUFA added to parenteral nutrition in protecting leukemia patients from severe enterocolitis. Fourteen patients with acute myeloid leukemia who received omega-3 PUFA in a Phase II trial were compared with 66 consecutive control patients not getting this intervention. We performed crude and adjusted comparisons, using inverse probability of treatment weighting for adjusted analysis, and blind outcome assessment to minimize assessor bias. Primary outcome was severe enterocolitis (≥Grade 3). The crude odds ratio of Grade 3 colitis or higher was 1.36 (95% CI 0.37 to 4.96, P = 0.64), and the adjusted odds ratio was 0.79 (95% CI 0.35 to 1.78, P = 0.57). There was little evidence to suggest differences between groups in serious adverse events and overall mortality. Our results provide little evidence that addition of omega-3 PUFA is beneficial in this condition. Routine treatment with omega-3 PUFA is currently not warranted.

Long-term comparison of everolimus-eluting stents with sirolimus- and paclitaxel-eluting stents for percutaneous coronary intervention of saphenous vein grafts

Aims: Newer-generation everolimus-eluting stents (EES) have been shown to improve clinical outcomes compared with early-generation sirolimus-eluting (SES) and paclitaxel-eluting stents (PES) in patients undergoing percutaneous coronary intervention (PCI). Whether this benefit is maintained among patients with saphenous vein graft (SVG) disease remains controversial. Methods and results: We assessed cumulative incidence rates (CIR) per 100 patient years after inverse probability of treatment weighting to compare clinical outcomes. The pre-specified primary endpoint was the composite of cardiac death, myocardial infarction (MI), and target vessel revascularisation (TVR). Out of 12,339 consecutively treated patients, 288 patients (5.7%) underwent PCI of at least one SVG lesion with EES (n=127), SES (n=103) or PES (n=58). Up to four years, CIR of the primary endpoint were 58.7 for EES, 45.2 for SES and 45.6 for PES with similar adjusted risks between groups (EES vs. SES; HR 0.94, 95% CI: 0.55-1.60, EES vs. PES; HR 1.07, 95% CI: 0.60-1.91). Adjusted risks showed no significant differences between stent types for cardiac death, MI and TVR. Conclusions: Among patients undergoing PCI for SVG lesions, newer-generation EES have similar safety and efficacy to early-generation SES and PES during long-term follow-up to four years.

Proton diffusion tensor spectroscopy of metabolites in human muscle in vivo

PURPOSE To study the apparent diffusivity and its directionality for metabolites of skeletal muscle in humans in vivo by (1) H magnetic resonance spectroscopy. METHODS The diffusion tensors were determined on a 3 Tesla MR system using optimized acquisition and processing methods including an adapted STEAM sequence with orientation-dependent diffusion weighting, pulse-triggering with individually adapted delays, eddy-current correction schemes, median filtering, and simultaneous prior-knowledge fitting of all related spectra. RESULTS The average apparent diffusivities, as well as the fractional anisotropies of taurine (ADCav  = 0.74 × 10(-3) s/mm(2) , FA = 0.46), creatine (ADCav  = 0.41 × 10(-3)  s/mm(2) , FA = 0.33), trimethylammonium compounds (ADCav  = 0.48 × 10(-3)  s/mm(2) , FA = 0.34), carnosine (ADCav  = 0.46 × 10(-3)  s/mm(2) , FA = 0.47), and water (ADCav  = 1.5 × 10(-3)  s/mm(2) , FA = 0.36) were estimated. The diffusivities of most metabolites and water were significantly different from each other. Diffusion was found to be anisotropic and the diffusion tensors showed tensor correlation coefficients close to 1 and were hence found to be essentially coaligned. The magnitudes of apparent metabolite diffusivities were largely ordered according to molecular weight, with taurine as the smallest molecule diffusing fastest, both along and across the fiber direction. CONCLUSION Diffusivities, directional dependence of diffusion and fractional anisotropies of (1) H MRS-visible muscle metabolites were presented. It was shown that metabolites share diffusion directionality with water and have similar fractional anisotropies, hinting at similar diffusion barriers. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.

Weber fractions and time-order errors for long and short durations: Implications for modeling

Using a weighted up-down procedure, in each of eight conditions 28 participants compared durations of auditory (noise bursts) or visual (LED flashes) intervals; filled or unfilled with 3-ms markers; with or without feedback. Standards (Sts) were 100 and 1000 ms, and the ISI 900 ms. Intermixedly, presentation orders were St-Comparison (Co) and Co-St. TOEs were positive for St=100-ms and negative for St=1000 ms. Weber fractions (WFs, JND/St) were lowered by feedback. For visual-filled and visual-empty, WFs were highest for St=100 ms. For auditory-filled and visual-empty, St interacted with Order: lowest WFs occurred for St-Co with St=1000 ms, but for Co-St with St=100 ms. Lowest average WFs occurred with St-Co for visual-filled, but with Co-St for visual-empty. The results refute the generalization of better discrimination with St-Co than with Co-St (”type-B effect”), and support the notion of sensation weighting: flexibly differential impact weights of the compared durations in generating the response.

Robust Denoising using Feature and Color Information

We propose a method that robustly combines color and feature buffers to denoise Monte Carlo renderings. On one hand, feature buffers, such as per pixel normals, textures, or depth, are effective in determining denoising filters because features are highly correlated with rendered images. Filters based solely on features, however, are prone to blurring image details that are not well represented by the features. On the other hand, color buffers represent all details, but they may be less effective to determine filters because they are contaminated by the noise that is supposed to be removed. We propose to obtain filters using a combination of color and feature buffers in an NL-means and cross-bilateral filtering framework. We determine a robust weighting of colors and features using a SURE-based error estimate. We show significant improvements in subjective and quantitative errors compared to the previous state-of-the-art. We also demonstrate adaptive sampling and space-time filtering for animations.