GENEHUNTER: your 'one-stop shop' for statistical genetic analysis?

The past decade has brought a proliferation of statistical genetic (linkage) analysis techniques, incorporating new methodology and/or improvement of existing methodology in gene mapping, specifically targeted towards the localization of genes underlying complex disorders. Most of these techniques have been implemented in user-friendly programs and made freely available to the genetics community. Although certain packages may be more 'popular' than others, a common question asked by genetic researchers is 'which program is best for me?'. To help researchers answer this question, the following software review aims to summarize the main advantages and disadvantages of the popular GENEHUNTER package.

Quality of life after early enteral feeding versus standard care for proven or suspected advanced epithelial ovarian cancer: Results from a randomised trial

Background Malnutrition is common in patients with advanced epithelial ovarian cancer (EOC), and is associated with impaired quality of life (QoL), longer hospital stay and higher risk of treatment-related adverse events. This phase III multi-centre randomised clinical trial tested early enteral feeding versus standard care on postoperative QoL. Methods From 2009 to 2013, 109 patients requiring surgery for suspected advanced EOC, moderately to severely malnourished were enrolled at five sites across Queensland and randomised to intervention (n = 53) or control (n = 56) groups. Intervention involved intraoperative nasojejunal tube placement and enteral feeding until adequate oral intake could be maintained. Despite being randomised to intervention, 20 patients did not receive feeds (13 did not receive the feeding tube; 7 had it removed early). Control involved postoperative diet as tolerated. QoL was measured at baseline, 6 weeks postoperatively and 30 days after the third cycle of chemotherapy. The primary outcome measure was the difference in QoL between the intervention and the control group. Secondary endpoints included treatment-related adverse event occurrence, length of stay, postoperative services use, and nutritional status. Results Baseline characteristics were comparable between treatment groups. No significant difference in QoL was found between the groups at any time point. There was a trend towards better nutritional status in patients who received the intervention but the differences did not reach statistical significance except for the intention-to-treat analysis at 7 days postoperatively (11.8 intervention vs. 13.8 control, p 0.04). Conclusion Early enteral feeding did not significantly improve patients' QoL compared to standard of care but may improve nutritional status.

Elevated levels of PFOS and PFHxS in firefighters exposed to aqueous film forming foam (AFFF)

Exposure to aqueous film forming foam (AFFF) was evaluated in 149 firefighters working at AFFF training facilities in Australia by analysis of PFOS and related compounds in serum. A questionnaire was designed to capture information about basic demographic factors, lifestyle factors and potential occupational exposure (such as work history and self-reported skin contact with foam). The results showed that a number of factors were associated with PFAA serum concentrations. Blood donation was found to be linked to low PFAA levels, and the concentrations of PFOS and PFHxS were found to be positively associated with years of jobs with AFFF contact. The highest levels of PFOS and PFHxS were one order of magnitude higher compared to the general population in Australia and Canada. Study participants who had worked ten years or less had levels of PFOS that were similar to or only slightly above those of the general population. This coincides with the phase out of 3M AFFF from all training facilities in 2003, and suggests that the exposures to PFOS and PFHxS in AFFF have declined in recent years. Self-reporting of skin contact and frequency of contact were used as an index of exposure. Using this index, there was no relationship between PFOS levels and skin exposure. This index of exposure is limited as it relies on self-report and it only considers skin exposure to AFFF, and does not capture other routes of potential exposure. Possible associations between serum PFAA concentrations and five biochemical outcomes were assessed. The outcomes were serum cholesterol, triglycerides, high-density lipoproteins, low density lipoproteins, and uric acid. No statistical associations between any of these endpoints and serum PFAA concentrations were observed.

Novel fluorinated surfactants tentatively identified in firefighters using liquid chromatography quadrupole time-of flight tandem mass spectrometry and a case-control approach

Fluorinated surfactant-based aqueous film-forming foams (AFFFs) are made up of per- and polyfluorinated alkyl substances (PFAS) and are used to extinguish fires involving highly flammable liquids. The use of perfluorooctanesulfonic acid (PFOS) and other perfluoroalkyl acids (PFAAs) in some AFFF formulations has been linked to substantial environmental contamination. Recent studies have identified a large number of novel and infrequently reported fluorinated surfactants in different AFFF formulations. In this study, a strategy based on a case-control approach using quadrupole time-of-flight tandem mass spectrometry (QTOF-MS/MS) and advanced statistical methods has been used to extract and identify known and unknown PFAS in human serum associated with AFFF-exposed firefighters. Two target sulfonic acids [PFOS and perfluorohexanesulfonic acid (PFHxS)], three non-target acids [perfluoropentanesulfonic acid (PFPeS), perfluoroheptanesulfonic acid (PFHpS), and perfluorononanesulfonic acid (PFNS)], and four unknown sulfonic acids (Cl-PFOS, ketone-PFOS, ether-PFHxS, and Cl-PFHxS) were exclusively or significantly more frequently detected at higher levels in firefighters compared to controls. The application of this strategy has allowed for identification of previously unreported fluorinated chemicals in a timely and cost-efficient way.

Patient preferences for receiving remote communication support for lifestyle physical activity behaviour change: The perspective of patients with musculoskeletal disorders from three hospital services

This study examined patients’ preference ratings for receiving support via remote communication to increase their lifestyle physical activity. Methods People with musculoskeletal disorders ( n=221 of 296 eligible) accessing one of three clinics provided preference ratings for “how much” they wanted to receive physical activity support via five potential communication modalities. The five ratings were generated on a horizontal analogue rating scale (0 represented “not at all”; 10 represented “very much”). Results Most (n=155, 70%) desired referral to a physical activity promoting intervention. “Print and post” communications had the highest median preference rating (7/10), followed by email and telephone (both 5/10), text messaging (1/10), and private Internet-based social network messages (0/10). Desire to be referred was associated with higher preference for printed materials (coefficient = 2.739, p<0.001), telephone calls (coefficient = 3.000, p<0.001), and email (coefficient = 2.059, p=0.02). Older age was associated with lower preference for email (coefficient = −0.100, p<0.001), texting (coefficient = −0.096, p<0.001), and social network messages (coefficient = −0.065, p<0.001). Conclusion Patients desiring support to be physically active indicated preferences for interventions with communication via print, email, or telephone calls.

Information preferences for the evaluation of coastal development impacts on ecosystem services: A multi-criteria assessment in the Australian context

Ecosystem based management requires the integration of various types of assessment indicators. Understanding stakeholders' information preferences is important, in selecting those indicators that best support management and policy. Both the preferences of decision-makers and the general public may matter, in democratic participatory management institutions. This paper presents a multi-criteria analysis aimed at quantifying the relative importance to these groups of economic, ecological and socio-economic indicators usually considered when managing ecosystem services in a coastal development context. The Analytic Hierarchy Process (AHP) is applied within two nationwide surveys in Australia, and preferences of both the general public and decision-makers for these indicators are elicited and compared. Results show that, on average across both groups, the priority in assessing a generic coastal development project is for the ecological assessment of its impacts on marine biodiversity. Ecological assessment indicators are globally preferred to both economic and socio-economic indicators regardless of the nature of the impacts studied. These results are observed for a significantly larger proportion of decision-maker than general public respondents, questioning the extent to which the general public's preferences are well reflected in decision-making processes.

Re-examination of one-point methods of liquid limit determination

This Paper deals with the analysis of liquid limit of soils, an inferential parameter of universal acceptance. It has been undertaken primarily to re-examine one-point methods of determination of liquid limit water contents. It has been shown by basic characteristics of soils and associated physico-chemical factors that critical shear strengths at liquid limit water contents arise out of force field equilibrium and are independent of soil type. This leads to the formation of a scientific base for liquid limit determination by one-point methods, which hitherto was formulated purely on statistical analysis of data. Available methods (Norman, 1959; Karlsson, 1961; Clayton & Jukes, 1978) of one-point liquid limit determination have been critically re-examined. A simple one-point cone penetrometer method of computing liquid limit has been suggested and compared with other methods. Experimental data of Sherwood & Ryley (1970) have been employed for comparison of different cone penetration methods. Results indicate that, apart from mere statistical considerations, one-point methods have a strong scientific base on the uniqueness of modified flow line irrespective of soil type. Normalized flow line is obtained by normalization of water contents by liquid limit values thereby nullifying the effects of surface areas and associated physico-chemical factors that are otherwise reflected in different responses at macrolevel.Cet article traite de l'analyse de la limite de liquidité des sols, paramètre déductif universellement accepté. Cette analyse a été entreprise en premier lieu pour ré-examiner les méthodes à un point destinées à la détermination de la teneur en eau à la limite de liquidité. Il a été démontré par les caractéristiques fondamentales de sols et par des facteurs physico-chimiques associés que les résistances critiques à la rupture au cisaillement pour des teneurs en eau à la limite de liquidité résultent de l'équilibre des champs de forces et sont indépendantes du type de sol concerné. On peut donc constituer une base scientifique pour la détermination de la limite de liquidité par des méthodes à un point lesquelles, jusqu'alors, n'avaient été formulées que sur la base d'une analyse statistique des données. Les méthodes dont on dispose (Norman, 1959; Karlsson, 1961; Clayton & Jukes, 1978) pour la détermination de la limite de liquidité à un point font l'objet d'un ré-examen critique. Une simple méthode d'analyse à un point à l'aide d'un pénétromètre à cône pour le calcul de la limite de liquidité a été suggérée et comparée à d'autres méthodes. Les données expérimentales de Sherwood & Ryley (1970) ont été utilisées en vue de comparer différentes méthodes de pénétration par cône. En plus de considérations d'ordre purement statistque, les résultats montrent que les méthodes de détermination à un point constituent une base scientifique solide en raison du caractère unique de la ligne de courant modifiée, quel que soit le type de sol La ligne de courant normalisée est obtenue par la normalisation de la teneur en eau en faisant appel à des valeurs de limite de liquidité pour, de cette manière, annuler les effets des surfaces et des facteurs physico-chimiques associés qui sans cela se manifesteraient dans les différentes réponses au niveau macro.

Noah Benevolent Society records, undated, 1852-1979.

Collection consists of several versions of the constitution; minute books of the membership meetings (1852-1856, 1868-1907, 1914-1971; until 1907 in German, afterwards in English); minute books of meetings of the trustees (1852-1858, 1876-1974, until 1912 in German); an index to and summary of the trustees minutes (1927-1944); several anniversary journals starting with the 50th, which was also "the first extant history of the Noah Benevolent Society"; membership books (1861-1892, 1930-1965, until 1892 in German; the books after 1930 contain detailed information concerning each member's age, occupation, family, military service, etc.); financial records (1862-1870, 1964-1967, 1972); quarterly accountant's reports (bound with the membership minutes); monthly financial and statistical reports of the Mordechai Federal Credit Union (March 1959-June 1960) established by the Society; lists and addresses of members; newsletters (1927-1979) and other material and photographs reflecting the Society's activities.

Statistical significance of sequential firing patterns in multi-neuronal spike trains

Sequential firings with fixed time delays are frequently observed in simultaneous recordings from multiple neurons. Such temporal patterns are potentially indicative of underlying microcircuits and it is important to know when a repeatedly occurring pattern is statistically significant. These sequences are typically identified through correlation counts. In this paper we present a method for assessing the significance of such correlations. We specify the null hypothesis in terms of a bound on the conditional probabilities that characterize the influence of one neuron on another. This method of testing significance is more general than the currently available methods since under our null hypothesis we do not assume that the spiking processes of different neurons are independent. The structure of our null hypothesis also allows us to rank order the detected patterns. We demonstrate our method on simulated spike trains.

Bayesian statistical analysis of bacterial diversity

Bacteria play an important role in many ecological systems. The molecular characterization of bacteria using either cultivation-dependent or cultivation-independent methods reveals the large scale of bacterial diversity in natural communities, and the vastness of subpopulations within a species or genus. Understanding how bacterial diversity varies across different environments and also within populations should provide insights into many important questions of bacterial evolution and population dynamics. This thesis presents novel statistical methods for analyzing bacterial diversity using widely employed molecular fingerprinting techniques. The first objective of this thesis was to develop Bayesian clustering models to identify bacterial population structures. Bacterial isolates were identified using multilous sequence typing (MLST), and Bayesian clustering models were used to explore the evolutionary relationships among isolates. Our method involves the inference of genetic population structures via an unsupervised clustering framework where the dependence between loci is represented using graphical models. The population dynamics that generate such a population stratification were investigated using a stochastic model, in which homologous recombination between subpopulations can be quantified within a gene flow network. The second part of the thesis focuses on cluster analysis of community compositional data produced by two different cultivation-independent analyses: terminal restriction fragment length polymorphism (T-RFLP) analysis, and fatty acid methyl ester (FAME) analysis. The cluster analysis aims to group bacterial communities that are similar in composition, which is an important step for understanding the overall influences of environmental and ecological perturbations on bacterial diversity. A common feature of T-RFLP and FAME data is zero-inflation, which indicates that the observation of a zero value is much more frequent than would be expected, for example, from a Poisson distribution in the discrete case, or a Gaussian distribution in the continuous case. We provided two strategies for modeling zero-inflation in the clustering framework, which were validated by both synthetic and empirical complex data sets. We show in the thesis that our model that takes into account dependencies between loci in MLST data can produce better clustering results than those methods which assume independent loci. Furthermore, computer algorithms that are efficient in analyzing large scale data were adopted for meeting the increasing computational need. Our method that detects homologous recombination in subpopulations may provide a theoretical criterion for defining bacterial species. The clustering of bacterial community data include T-RFLP and FAME provides an initial effort for discovering the evolutionary dynamics that structure and maintain bacterial diversity in the natural environment.

Statistical and Information-Theoretic Methods for Data-Analysis

In this Thesis, we develop theory and methods for computational data analysis. The problems in data analysis are approached from three perspectives: statistical learning theory, the Bayesian framework, and the information-theoretic minimum description length (MDL) principle. Contributions in statistical learning theory address the possibility of generalization to unseen cases, and regression analysis with partially observed data with an application to mobile device positioning. In the second part of the Thesis, we discuss so called Bayesian network classifiers, and show that they are closely related to logistic regression models. In the final part, we apply the MDL principle to tracing the history of old manuscripts, and to noise reduction in digital signals.

Computational Methods for Locating and Analyzing Conserved Gene Regulatory DNA Elements

This thesis presents methods for locating and analyzing cis-regulatory DNA elements involved with the regulation of gene expression in multicellular organisms. The regulation of gene expression is carried out by the combined effort of several transcription factor proteins collectively binding the DNA on the cis-regulatory elements. Only sparse knowledge of the 'genetic code' of these elements exists today. An automatic tool for discovery of putative cis-regulatory elements could help their experimental analysis, which would result in a more detailed view of the cis-regulatory element structure and function. We have developed a computational model for the evolutionary conservation of cis-regulatory elements. The elements are modeled as evolutionarily conserved clusters of sequence-specific transcription factor binding sites. We give an efficient dynamic programming algorithm that locates the putative cis-regulatory elements and scores them according to the conservation model. A notable proportion of the high-scoring DNA sequences show transcriptional enhancer activity in transgenic mouse embryos. The conservation model includes four parameters whose optimal values are estimated with simulated annealing. With good parameter values the model discriminates well between the DNA sequences with evolutionarily conserved cis-regulatory elements and the DNA sequences that have evolved neutrally. In further inquiry, the set of highest scoring putative cis-regulatory elements were found to be sensitive to small variations in the parameter values. The statistical significance of the putative cis-regulatory elements is estimated with the Two Component Extreme Value Distribution. The p-values grade the conservation of the cis-regulatory elements above the neutral expectation. The parameter values for the distribution are estimated by simulating the neutral DNA evolution. The conservation of the transcription factor binding sites can be used in the upstream analysis of regulatory interactions. This approach may provide mechanistic insight to the transcription level data from, e.g., microarray experiments. Here we give a method to predict shared transcriptional regulators for a set of co-expressed genes. The EEL (Enhancer Element Locator) software implements the method for locating putative cis-regulatory elements. The software facilitates both interactive use and distributed batch processing. We have used it to analyze the non-coding regions around all human genes with respect to the orthologous regions in various other species including mouse. The data from these genome-wide analyzes is stored in a relational database which is used in the publicly available web services for upstream analysis and visualization of the putative cis-regulatory elements in the human genome.