Quantitative genetic modeling and inference in the presence of nonignorable missing data.

Natural selection is typically exerted at some specific life stages. If natural selection takes place before a trait can be measured, using conventional models can cause wrong inference about population parameters. When the missing data process relates to the trait of interest, a valid inference requires explicit modeling of the missing process. We propose a joint modeling approach, a shared parameter model, to account for nonrandom missing data. It consists of an animal model for the phenotypic data and a logistic model for the missing process, linked by the additive genetic effects. A Bayesian approach is taken and inference is made using integrated nested Laplace approximations. From a simulation study we find that wrongly assuming that missing data are missing at random can result in severely biased estimates of additive genetic variance. Using real data from a wild population of Swiss barn owls Tyto alba, our model indicates that the missing individuals would display large black spots; and we conclude that genes affecting this trait are already under selection before it is expressed. Our model is a tool to correctly estimate the magnitude of both natural selection and additive genetic variance.

24 Hours in the Life of HIV-1 in a T Cell Line.

HIV-1 infects CD4+ T cells and completes its replication cycle in approximately 24 hours. We employed repeated measurements in a standardized cell system and rigorous mathematical modeling to characterize the emergence of the viral replication intermediates and their impact on the cellular transcriptional response with high temporal resolution. We observed 7,991 (73%) of the 10,958 expressed genes to be modulated in concordance with key steps of viral replication. Fifty-two percent of the overall variability in the host transcriptome was explained by linear regression on the viral life cycle. This profound perturbation of cellular physiology was investigated in the light of several regulatory mechanisms, including transcription factors, miRNAs, host-pathogen interaction, and proviral integration. Key features were validated in primary CD4+ T cells, and with viral constructs using alternative entry strategies. We propose a model of early massive cellular shutdown and progressive upregulation of the cellular machinery to complete the viral life cycle.

Nava enhances ventilatory variability and diaphragmatic activity/tidal volume coupling

INTRODUCTION. Neurally Adjusted Ventilatory Assist (NAVA) is a new ventilatory mode in which ventilator settings are adjusted based on the electrical activity detected in the diaphragm (Eadi). This mode offers significant advantages in mechanical ventilation over standard pressure support (PS) modes, since ventilator input is determined directly from patient ventilatory demand. Therefore, it is expected that tidal volume (Vt) under NAVA would show better correlation with Eadi compared with PS, and exhibit greater variability due to the variability in the Eadi input to the ventilator. OBJECTIVES. To compare tidal volume variability in PS and NAVA ventilation modes, and its correlation with patient ventilatory demand (as characterized by maximum Eadi). METHODS. Acomparative study of patient-ventilator interaction was performed for 22 patients during standard PS with clinician determined ventilator settings; and NAVA, with NAVA gain set to ensure the same peak airway pressure as the total pressure obtained in PS. A 20 min continuous recording was performed in each ventilator mode. Respiratory rate, Vt, and Eadi were recorded. Tidal volume variance and Pearson correlation coefficient between Vt and Eadi were calculated for each patient. A periodogram was plotted for each ventilator mode and each patient, showing spectral power as a function of frequency to assess variability. RESULTS. Median, lower quartile and upper quartile values for Vt variance and Vt/Eadi correlation are shown in Table 1. The NAVA cohort exhibits substantially greater correlation and variance than the PS cohort. Power spectrums for Vt and Eadi are shown in Fig. 1 (PS and NAVA) for a typical patient. The enlarged section highlights how changes in Eadi are highly synchronized with NAVA ventilation, but less so for PS. CONCLUSIONS. There is greater variability in tidal volume and correlation between tidal volume and diaphragmatic electrical activity with NAVA compared to PS. These results are consistent with the improved patient-ventilator synchrony reported in the literature.

A deterministic model to assess the impact of AIDS interventions in countries with generalized HIV epidemic. An application to Botswana

General introductionThe Human Immunodeficiency/Acquired Immunodeficiency Syndrome (HIV/AIDS) epidemic, despite recent encouraging announcements by the World Health Organization (WHO) is still today one of the world's major health care challenges.The present work lies in the field of health care management, in particular, we aim to evaluate the behavioural and non-behavioural interventions against HIV/AIDS in developing countries through a deterministic simulation model, both in human and economic terms. We will focus on assessing the effectiveness of the antiretroviral therapies (ART) in heterosexual populations living in lesser developed countries where the epidemic has generalized (formerly defined by the WHO as type II countries). The model is calibrated using Botswana as a case study, however our model can be adapted to other countries with similar transmission dynamics.The first part of this thesis consists of reviewing the main mathematical concepts describing the transmission of infectious agents in general but with a focus on human immunodeficiency virus (HIV) transmission. We also review deterministic models assessing HIV interventions with a focus on models aimed at African countries. This review helps us to recognize the need for a generic model and allows us to define a typical structure of such a generic deterministic model.The second part describes the main feed-back loops underlying the dynamics of HIV transmission. These loops represent the foundation of our model. This part also provides a detailed description of the model, including the various infected and non-infected population groups, the type of sexual relationships, the infection matrices, important factors impacting HIV transmission such as condom use, other sexually transmitted diseases (STD) and male circumcision. We also included in the model a dynamic life expectancy calculator which, to our knowledge, is a unique feature allowing more realistic cost-efficiency calculations. Various intervention scenarios are evaluated using the model, each of them including ART in combination with other interventions, namely: circumcision, campaigns aimed at behavioral change (Abstain, Be faithful or use Condoms also named ABC campaigns), and treatment of other STD. A cost efficiency analysis (CEA) is performed for each scenario. The CEA consists of measuring the cost per disability-adjusted life year (DALY) averted. This part also describes the model calibration and validation, including a sensitivity analysis.The third part reports the results and discusses the model limitations. In particular, we argue that the combination of ART and ABC campaigns and ART and treatment of other STDs are the most cost-efficient interventions through 2020. The main model limitations include modeling the complexity of sexual relationships, omission of international migration and ignoring variability in infectiousness according to the AIDS stage.The fourth part reviews the major contributions of the thesis and discusses model generalizability and flexibility. Finally, we conclude that by selecting the adequate interventions mix, policy makers can significantly reduce the adult prevalence in Botswana in the coming twenty years providing the country and its donors can bear the cost involved.Part I: Context and literature reviewIn this section, after a brief introduction to the general literature we focus in section two on the key mathematical concepts describing the transmission of infectious agents in general with a focus on HIV transmission. Section three provides a description of HIV policy models, with a focus on deterministic models. This leads us in section four to envision the need for a generic deterministic HIV policy model and briefly describe the structure of such a generic model applicable to countries with generalized HIV/AIDS epidemic, also defined as pattern II countries by the WHO.

Temporal variability of antibiotics fluxes in wastewater and contribution from hospitals.

Significant quantities of antibiotics are used in all parts of the globe to treat diseases with bacterial origins. After ingestion, antibiotics are excreted by the patient and transmitted in due course to the aquatic environment. This study examined temporal fluctuations (monthly time scale) in antibiotic sources (ambulatory sales and data from a hospital dispensary) for Lausanne, Switzerland. Source variability (i.e., antibiotic consumption, monthly data for 2006-2010) were examined in detail for nine antibiotics--azithromycin, ciprofloxacin, clarithromycin, clindamycin, metronidazole, norfloxacin, ofloxacin, sulfamethoxazole and trimethoprim, from which two main conclusions were reached. First, some substances--azithromycin, clarithromycin, ciprofloxacin--displayed high seasonality in their consumption, with the winter peak being up to three times higher than the summer minimum. This seasonality in consumption resulted in seasonality in Predicted Environmental Concentrations (PECs). In addition, the seasonality in PECs was also influenced by that in the base wastewater flow. Second, the contribution of hospitals to the total load of antibiotics reaching the Lausanne Wastewater Treatment Plant (WTP) fluctuated markedly on a monthly time scale, but with no seasonal pattern detected. That is, there was no connection between fluctuations in ambulatory and hospital consumption for the substances investigated.

Modeling stochasticity and robustness in gene regulatory networks.

MOTIVATION: Understanding gene regulation in biological processes and modeling the robustness of underlying regulatory networks is an important problem that is currently being addressed by computational systems biologists. Lately, there has been a renewed interest in Boolean modeling techniques for gene regulatory networks (GRNs). However, due to their deterministic nature, it is often difficult to identify whether these modeling approaches are robust to the addition of stochastic noise that is widespread in gene regulatory processes. Stochasticity in Boolean models of GRNs has been addressed relatively sparingly in the past, mainly by flipping the expression of genes between different expression levels with a predefined probability. This stochasticity in nodes (SIN) model leads to over representation of noise in GRNs and hence non-correspondence with biological observations. RESULTS: In this article, we introduce the stochasticity in functions (SIF) model for simulating stochasticity in Boolean models of GRNs. By providing biological motivation behind the use of the SIF model and applying it to the T-helper and T-cell activation networks, we show that the SIF model provides more biologically robust results than the existing SIN model of stochasticity in GRNs. AVAILABILITY: Algorithms are made available under our Boolean modeling toolbox, GenYsis. The software binaries can be downloaded from http://si2.epfl.ch/ approximately garg/genysis.html.

Effects of Different Postural Conditions on Handwriting Variability

During their career, forensic document examiners will inevitably be confronted with handwriting carried out under unusual conditions (UnC). A questioned document signed on top of a car or on a vertical surface like a wall are two examples. These atypical circumstances may give rise to more variability of the signatures or written words, in particular if the body was in non-traditional writing position without the traditional support. Few studies were devoted to handwriting variability under unusual writing conditions. The current study investigates whether individual variability changes with special writing conditions. In a previous study (Sciacca & al, 2009), we found that eight repetitions were sufficient to obtain a correct estimation of the variance. In the present study, twelve subjects were asked to write two word sets eight times in upper and eight times in lower case, under different conditions : sitting and writing on a horizontal (usual condition UC) or vertical support; and standing, kneeling or laying while writing on a horizontal or vertical support (unusual conditions UnC). Words were written on a pen tablet, normalized in space and time and then averaged. The variance of the eight words was measured under all conditions. Results showed only an increase in variability under the laying and kneeling / vertical UnC. Within the five other postural conditions tested, handwriting was shown to be very stable.

Homology modeling and metabolism prediction of human carboxylesterase-2 using docking analyses by GriDock: a parallelized tool based on AutoDock 4.0.

Metabolic problems lead to numerous failures during clinical trials, and much effort is now devoted to developing in silico models predicting metabolic stability and metabolites. Such models are well known for cytochromes P450 and some transferases, whereas less has been done to predict the activity of human hydrolases. The present study was undertaken to develop a computational approach able to predict the hydrolysis of novel esters by human carboxylesterase hCES2. The study involved first a homology modeling of the hCES2 protein based on the model of hCES1 since the two proteins share a high degree of homology (congruent with 73%). A set of 40 known substrates of hCES2 was taken from the literature; the ligands were docked in both their neutral and ionized forms using GriDock, a parallel tool based on the AutoDock4.0 engine which can perform efficient and easy virtual screening analyses of large molecular databases exploiting multi-core architectures. Useful statistical models (e.g., r (2) = 0.91 for substrates in their unprotonated state) were calculated by correlating experimental pK(m) values with distance between the carbon atom of the substrate's ester group and the hydroxy function of Ser228. Additional parameters in the equations accounted for hydrophobic and electrostatic interactions between substrates and contributing residues. The negatively charged residues in the hCES2 cavity explained the preference of the enzyme for neutral substrates and, more generally, suggested that ligands which interact too strongly by ionic bonds (e.g., ACE inhibitors) cannot be good CES2 substrates because they are trapped in the cavity in unproductive modes and behave as inhibitors. The effects of protonation on substrate recognition and the contrasting behavior of substrates and products were finally investigated by MD simulations of some CES2 complexes.

The cover basement contact beneath the Rawil axial depression (Western Alps) - True amplitude seismic processing, petrophysical properties, and modeling

Since 1986, several near-vertical seismic reflection profiles have been recorded in Switzerland in order to map the deep geologic structure of the Alps. One objective of this endeavour has been to determine the geometries of the autochthonous basement and of the external crystalline massifs, important elements for understanding the geodynamics of the Alpine orogeny. The PNR-20 seismic line W1, located in the Rawil depression of the western Swiss Alps, provides important information on this subject. It extends northward from the `'Penninic front'' across the Helvetic nappes to the Prealps. The crystalline massifs do not outcrop along this profile. Thus, the interpretation of `'near-basement'' reflections has to be constrained by down-dip projections of surface geology, `'true amplitude'' processing, rock physical property studies and modelling. 3-D seismic modelling has been used to evaluate the seismic response of two alternative down-dip projection models. To constrain the interpretation in the southern part of the profile, `'true amplitude'' processing has provided information on the strength of the reflections. Density and velocity measurements on core samples collected up-dip from the region of the seismic line have been used to evaluate reflection coefficients of typical lithologic boundaries in the region. The cover-basement contact itself is not a source of strong reflections, but strong reflections arise from within the overlaying metasedimentary cover sequence, allowing the geometry of the top of the basement to be determined on the basis of `'near-basement'' reflections. The front of the external crystalline massifs is shown to extend beneath the Prealps, about 6 km north of the expected position. A 2-D model whose seismic response shows reflection patterns very similar to the observed is proposed.

Variability of ascending aorta diameter measurements as assessed with electrocardiography-gated multidetector computerized tomography and computer assisted diagnosis software.

Recently, morphometric measurements of the ascending aorta have been done with ECG-gated multidector computerized tomography (MDCT) to help the development of future novel transcatheter therapies (TCT); nevertheless, the variability of such measurements remains unknown. Thirty patients referred for ECG-gated CT thoracic angiography were evaluated. Continuous reformations of the ascending aorta, perpendicular to the centerline, were obtained automatically with a commercially available computer aided diagnosis (CAD). Then measurements of the maximal diameter were done with the CAD and manually by two observers (separately). Measurements were repeated one month later. The Bland-Altman method, Spearman coefficients, and a Wilcoxon signed-rank test were used to evaluate the variability, the correlation, and the differences between observers. The interobserver variability for maximal diameter between the two observers was up to 1.2 mm with limits of agreement [-1.5, +0.9] mm; whereas the intraobserver limits were [-1.2, +1.0] mm for the first observer and [-0.8, +0.8] mm for the second observer. The intraobserver CAD variability was 0.8 mm. The correlation was good between observers and the CAD (0.980-0.986); however, significant differences do exist (P<0.001). The maximum variability observed was 1.2 mm and should be considered in reports of measurements of the ascending aorta. The CAD is as reproducible as an experienced reader.

Genetic variability in a population of arbuscular mycorrhizal fungi causes variation in plant growth.

Different species of arbuscular mycorrhizal fungi (AMF) alter plant growth and affect plant coexistence and diversity. Effects of within-AMF species or within-population variation on plant growth have received less attention. High genetic variation exists within AMF populations. However, it is unknown whether genetic variation contributes to differences in plant growth. In our study, a population of AMF was cultivated under identical conditions for several generations prior to the experiments thus avoiding environmental maternal effects. We show that genetically different Glomus intraradices isolates from one AMF population significantly alter plant growth in an axenic system and in greenhouse experiments. Isolates increased or reduced plant growth meaning that plants potentially receive benefits or are subject to costs by forming associations with different individuals in the AMF population. This shows that genetic variability in AMF populations could affect host-plant fitness and should be considered in future research to understand these important soil organisms.