A BAYESIAN APPROACH TO DOSE-RESPONSE ASSESSMENT AND DRUG-DRUG INTERACTION ANALYSIS: APPLICATION TO IN VITRO STUDIES

The considerable search for synergistic agents in cancer research is motivated by the therapeutic benefits achieved by combining anti-cancer agents. Synergistic agents make it possible to reduce dosage while maintaining or enhancing a desired effect. Other favorable outcomes of synergistic agents include reduction in toxicity and minimizing or delaying drug resistance. Dose-response assessment and drug-drug interaction analysis play an important part in the drug discovery process, however analysis are often poorly done. This dissertation is an effort to notably improve dose-response assessment and drug-drug interaction analysis. The most commonly used method in published analysis is the Median-Effect Principle/Combination Index method (Chou and Talalay, 1984). The Median-Effect Principle/Combination Index method leads to inefficiency by ignoring important sources of variation inherent in dose-response data and discarding data points that do not fit the Median-Effect Principle. Previous work has shown that the conventional method yields a high rate of false positives (Boik, Boik, Newman, 2008; Hennessey, Rosner, Bast, Chen, 2010) and, in some cases, low power to detect synergy. There is a great need for improving the current methodology. We developed a Bayesian framework for dose-response modeling and drug-drug interaction analysis. First, we developed a hierarchical meta-regression dose-response model that accounts for various sources of variation and uncertainty and allows one to incorporate knowledge from prior studies into the current analysis, thus offering a more efficient and reliable inference. Second, in the case that parametric dose-response models do not fit the data, we developed a practical and flexible nonparametric regression method for meta-analysis of independently repeated dose-response experiments. Third, and lastly, we developed a method, based on Loewe additivity that allows one to quantitatively assess interaction between two agents combined at a fixed dose ratio. The proposed method makes a comprehensive and honest account of uncertainty within drug interaction assessment. Extensive simulation studies show that the novel methodology improves the screening process of effective/synergistic agents and reduces the incidence of type I error. We consider an ovarian cancer cell line study that investigates the combined effect of DNA methylation inhibitors and histone deacetylation inhibitors in human ovarian cancer cell lines. The hypothesis is that the combination of DNA methylation inhibitors and histone deacetylation inhibitors will enhance antiproliferative activity in human ovarian cancer cell lines compared to treatment with each inhibitor alone. By applying the proposed Bayesian methodology, in vitro synergy was declared for DNA methylation inhibitor, 5-AZA-2'-deoxycytidine combined with one histone deacetylation inhibitor, suberoylanilide hydroxamic acid or trichostatin A in the cell lines HEY and SKOV3. This suggests potential new epigenetic therapies in cell growth inhibition of ovarian cancer cells.

Safety of non-therapeutic atomoxetine exposures - a national poison data system study

AIMS This study's objective is to assess the safety of non-therapeutic atomoxetine exposures reported to the US National Poison Database System (NPDS). METHODS This is a retrospective database study of non-therapeutic single agent ingestions of atomoxetine in children and adults reported to the NPDS between 2002 and 2010. RESULTS A total of 20 032 atomoxetine exposures were reported during the study period, and 12 370 of these were single agent exposures. The median age was 9 years (interquartile range 3, 14), and 7380 were male (59.7%). Of the single agent exposures, 8813 (71.2%) were acute exposures, 3315 (26.8%) were acute-on-chronic, and 166 (1.3%) were chronic. In 10 608 (85.8%) cases, exposure was unintentional, in 1079 (8.7%) suicide attempts, and in 629 (5.1%) cases abuse. Of these cases, 3633 (29.4 %) were managed at health-care facilities. Acute-on-chronic exposure was associated with an increased risk of a suicidal reason for exposure compared with acute ingestions (odds ratio 1.44, 95% confidence interval 1.26-1.65). Most common clinical effects were drowsiness or lethargy (709 cases; 5.7%), tachycardia (555; 4.5%), and nausea (388; 3.1%). Major toxicity was observed in 21 cases (seizures in nine (42.9%), tachycardia in eight (38.1%), coma in six (28.6%), and ventricular dysrhythmia in one case (4.8%)). CONCLUSIONS Non-therapeutic atomoxetine exposures were largely safe, but seizures were rarely observed.

Institutionalizing Intensive Family Preservation Services: A Strategy for Creating Staffing Standards Based on Projections of At-Risk Children from Referral Sources

In spite of new legislation and much public and professional interest, intensive family preservation service (IFPS) remains in a vulnerable position as compared to other child welfare services. This article details a method to project ideal IFPS caseloads as a function of children who are at-risk for placement by various referral sources. Using this approach, resource allocation for IFPS can be more nearly on equal ground with the traditional child welfare functions and help IFPS to assume its needed place as a core service in the child welfare continuum.

Sea Level Pressure Variability Over the Southern Indian Ocean Inferred from a Glaciochemical Record in Princess Elizabeth Land, East Antarctica

A 250-year, high-resolution, multivariate ice core record from LGB65 (70degrees50'07"S, 77degrees04'29"E; 1850 m asl), Princess Elizabeth Land (PEL), is used to investigate sea level pressure (SLP) variability over the southern Indian Ocean (SIO). Empirical orthogonal function (EOF) analysis reveals that the first EOF (EOF1) of the glaciochemical record from LGB65 represents most of the variability in sea salt throughout the 250-year record. EOF1 is negatively correlated (95% confidence level and higher) to instrumental mean sea level pressure (MSLP) at Kerguelen and New Amsterdam islands, SIO. On the basis of comparison with NCEP/NCAR reanalysis, strong correlations were found between sea-salt variations and a quasi-stationary low that lies to the north of Prydz Bay, SIO. Comparison with a 250-year-long summer transpolar index (STPI) inferred from sub-Antarctic tree ring records reveals strong coherency. Decadal-scale SLP variability over SIO suggests shifting of the polar vortex. Prominent decadal-scale deepening of the southern Indian Ocean low (SIOL) exists circa 1790, 1810, 1835, 1860, 1880, 1900, and 1940 A. D., continuously after the 1970s, and prominent weakening circa 1750, 1795, 1825, 1850, 1870, 1890, 1910, and 1955 A. D. The LGB65 sea-salt record is characterized by significant decadal-scale variability with a strong similar to21-year periodic structure (99.9% confidence level). The relationship between LGB65 sea salt and solar irradiance changes shows that this periodicity is possibly the solar Hale cycle ( 22 years).

5-year results comparing mineral trioxide aggregate and adhesive resin composite for root-end sealing in apical surgery

INTRODUCTION Recent meta-analyses of the outcome of apical surgery using modern techniques including microsurgical principles and high-power magnification have yielded higher rates of healing. However, the information is mainly based on 1- to 2-year follow-up data. The present prospective study was designed to re-examine a large sample of teeth treated with apical surgery after 5 years. METHODS Patients were recalled 5 years after apical surgery, and treated teeth were classified as healed or not healed based on clinical and radiographic examination. (The latter was performed independently by 3 observers). Two different methods of root-end preparation and filling (primary study parameters) were to be compared (mineral trioxide aggregate [MTA] vs adhesive resin composite [COMP]) without randomization. RESULTS A total of 271 patients and teeth from a 1-year follow-up sample of 339 could be re-examined after 5 years (dropout rate = 20.1%). The overall rate of healed cases was 84.5% with a significant difference (P = .0003) when comparing MTA (92.5%) and COMP (76.6%). The evaluation of secondary study parameters yielded no significant difference for healing outcome when comparing subcategories (ie, sex, age, type of tooth treated, post/screw, type of surgery). CONCLUSIONS The results from this prospective nonrandomized clinical study with a 5-year follow-up of 271 teeth indicate that MTA exhibited a higher healing rate than COMP in the longitudinal prognosis of root-end sealing.

Fully automatic segmentation of AP pelvis X-rays via random forest regression with efficient feature selection and hierarchical sparse shape composition

In clinical practice, traditional X-ray radiography is widely used, and knowledge of landmarks and contours in anteroposterior (AP) pelvis X-rays is invaluable for computer aided diagnosis, hip surgery planning and image-guided interventions. This paper presents a fully automatic approach for landmark detection and shape segmentation of both pelvis and femur in conventional AP X-ray images. Our approach is based on the framework of landmark detection via Random Forest (RF) regression and shape regularization via hierarchical sparse shape composition. We propose a visual feature FL-HoG (Flexible- Level Histogram of Oriented Gradients) and a feature selection algorithm based on trace radio optimization to improve the robustness and the efficacy of RF-based landmark detection. The landmark detection result is then used in a hierarchical sparse shape composition framework for shape regularization. Finally, the extracted shape contour is fine-tuned by a post-processing step based on low level image features. The experimental results demonstrate that our feature selection algorithm reduces the feature dimension in a factor of 40 and improves both training and test efficiency. Further experiments conducted on 436 clinical AP pelvis X-rays show that our approach achieves an average point-to-curve error around 1.2 mm for femur and 1.9 mm for pelvis.

Imputation of sequence level genotypes in the Franches-Montagnes horse breed

BACKGROUND A cost-effective strategy to increase the density of available markers within a population is to sequence a small proportion of the population and impute whole-genome sequence data for the remaining population. Increased densities of typed markers are advantageous for genome-wide association studies (GWAS) and genomic predictions. METHODS We obtained genotypes for 54 602 SNPs (single nucleotide polymorphisms) in 1077 Franches-Montagnes (FM) horses and Illumina paired-end whole-genome sequencing data for 30 FM horses and 14 Warmblood horses. After variant calling, the sequence-derived SNP genotypes (~13 million SNPs) were used for genotype imputation with the software programs Beagle, Impute2 and FImpute. RESULTS The mean imputation accuracy of FM horses using Impute2 was 92.0%. Imputation accuracy using Beagle and FImpute was 74.3% and 77.2%, respectively. In addition, for Impute2 we determined the imputation accuracy of all individual horses in the validation population, which ranged from 85.7% to 99.8%. The subsequent inclusion of Warmblood sequence data further increased the correlation between true and imputed genotypes for most horses, especially for horses with a high level of admixture. The final imputation accuracy of the horses ranged from 91.2% to 99.5%. CONCLUSIONS Using Impute2, the imputation accuracy was higher than 91% for all horses in the validation population, which indicates that direct imputation of 50k SNP-chip data to sequence level genotypes is feasible in the FM population. The individual imputation accuracy depended mainly on the applied software and the level of admixture.

A regional climate palaeosimulation for Europe in the period 1500–1990 – Part 2: Shortcomings and strengths of models and reconstructions

This study compares gridded European seasonal series of surface air temperature (SAT) and precipitation (PRE) reconstructions with a regional climate simulation over the period 1500–1990. The area is analysed separately for nine subareas that represent the majority of the climate diversity in the European sector. In their spatial structure, an overall good agreement is found between the reconstructed and simulated climate features across Europe, supporting consistency in both products. Systematic biases between both data sets can be explained by a priori known deficiencies in the simulation. Simulations and reconstructions, however, largely differ in the temporal evolution of past climate for European subregions. In particular, the simulated anomalies during the Maunder and Dalton minima show stronger response to changes in the external forcings than recorded in the reconstructions. Although this disagreement is to some extent expected given the prominent role of internal variability in the evolution of regional temperature and precipitation, a certain degree of agreement is a priori expected in variables directly affected by external forcings. In this sense, the inability of the model to reproduce a warm period similar to that recorded for the winters during the first decades of the 18th century in the reconstructions is indicative of fundamental limitations in the simulation that preclude reproducing exceptionally anomalous conditions. Despite these limitations, the simulated climate is a physically consistent data set, which can be used as a benchmark to analyse the consistency and limitations of gridded reconstructions of different variables. A comparison of the leading modes of SAT and PRE variability indicates that reconstructions are too simplistic, especially for precipitation, which is associated with the linear statistical techniques used to generate the reconstructions. The analysis of the co-variability between sea level pressure (SLP) and SAT and PRE in the simulation yields a result which resembles the canonical co-variability recorded in the observations for the 20th century. However, the same analysis for reconstructions exhibits anomalously low correlations, which points towards a lack of dynamical consistency between independent reconstructions.

A pharyngeal jaw evolutionary innovation facilitated extinction in Lake Victoria cichlids

Evolutionary innovations, traits that give species access to previously unoccupied niches, may promote speciation and adaptive radiation. Here, we show that such innovations can also result in competitive inferiority and extinction. We present evidence that the modified pharyngeal jaws of cichlid fishes and several marine fish lineages, a classic example of evolutionary innovation, are not universally beneficial. A large-scale analysis of dietary evolution across marine fish lineages reveals that the innovation compromises access to energy-rich predator niches. We show that this competitive inferiority shaped the adaptive radiation of cichlids in Lake Tanganyika and played a pivotal and previously unrecognized role in the mass extinction of cichlid fishes in Lake Victoria after Nile perch invasion.

Genome-wide association studies based on sequence-derived genotypes reveal new QTL associated with conformation and performance traits in the Franches-Montagnes horse breed

To identify novel quantitative trait loci (QTL) within horses, we performed genome-wide association studies (GWAS) based on sequence-level genotypes for conformation and performance traits in the Franches-Montagnes (FM) horse breed. Sequence-level genotypes of FM horses were derived by re-sequencing 30 key founders and imputing 50K data of genotyped horses. In total, we included 1077 FM horses genotyped for ~4 million SNPs and their respective de-regressed breeding values of the traits in the analysis. Based on this dataset, we identified a total of 14 QTL associated with 18 conformation traits and one performance trait. Therefore, our results suggest that the application of sequence-derived genotypes increases the power to identify novel QTL which were not identified previously based on 50K SNP chip data.

How specific is apprenticeship training? Evidence from inter-firm and occupational mobility after graduation

Do apprenticeships convey mainly general or also firm- and occupation-specific human capital? Specific human capital may allow for specialization gains, but may also lead to allocative inefficiency due to mobility barriers. We analyse the case of Switzerland, which combines a comprehensive, high-quality apprenticeship system with a lightly regulated labour market. To assess human capital transferability after standardized firm-based apprenticeship training, we analyse inter-firm and occupational mobility and their effects on post-training wages. Using a longitudinal data set based on the PISA 2000 survey, we find high inter-firm and low occupational mobility within one year after graduation. Accounting for endogenous changes, we find a negative effect of occupation changes on wages, but no significant wage effect for firm changes. This indicates that occupation-specific human capital is an important component of apprenticeship training and that skills are highly transferable within an occupational field.