Joint modelling of longitudinal and survival data on breast cancer

Tese de Doutoramento em Ciências (Especialidade em Matemática)

Metabolic engineering with multi-objective optimization of kinetic models

Kinetic models have a great potential for metabolic engineering applications. They can be used for testing which genetic and regulatory modifications can increase the production of metabolites of interest, while simultaneously monitoring other key functions of the host organism. This work presents a methodology for increasing productivity in biotechnological processes exploiting dynamic models. It uses multi-objective dynamic optimization to identify the combination of targets (enzymatic modifications) and the degree of up- or down-regulation that must be performed in order to optimize a set of pre-defined performance metrics subject to process constraints. The capabilities of the approach are demonstrated on a realistic and computationally challenging application: a large-scale metabolic model of Chinese Hamster Ovary cells (CHO), which are used for antibody production in a fed-batch process. The proposed methodology manages to provide a sustained and robust growth in CHO cells, increasing productivity while simultaneously increasing biomass production, product titer, and keeping the concentrations of lactate and ammonia at low values. The approach presented here can be used for optimizing metabolic models by finding the best combination of targets and their optimal level of up/down-regulation. Furthermore, it can accommodate additional trade-offs and constraints with great flexibility.

Development of computational and experimental methods for biomass composition and evaluation of its impact in genome-scale models prediction

The use of genome-scale metabolic models has been rapidly increasing in fields such as metabolic engineering. An important part of a metabolic model is the biomass equation since this reaction will ultimately determine the predictive capacity of the model in terms of essentiality and flux distributions. Thus, in order to obtain a reliable metabolic model the biomass precursors and their coefficients must be as precise as possible. Ideally, determination of the biomass composition would be performed experimentally, but when no experimental data are available this is established by approximation to closely related organisms. Computational methods however, can extract some information from the genome such as amino acid and nucleotide compositions. The main objectives of this study were to compare the biomass composition of several organisms and to evaluate how biomass precursor coefficients affected the predictability of several genome-scale metabolic models by comparing predictions with experimental data in literature. For that, the biomass macromolecular composition was experimentally determined and the amino acid composition was both experimentally and computationally estimated for several organisms. Sensitivity analysis studies were also performed with the Escherichia coli iAF1260 metabolic model concerning specific growth rates and flux distributions. The results obtained suggest that the macromolecular composition is conserved among related organisms. Contrasting, experimental data for amino acid composition seem to have no similarities for related organisms. It was also observed that the impact of macromolecular composition on specific growth rates and flux distributions is larger than the impact of amino acid composition, even when data from closely related organisms are used.

Predicting SO2 pollution incidents by means of additive models with optimum variable selection

The aim of this paper is to predict time series of SO2 concentrations emitted by coal-fired power stations in order to estimate in advance emission episodes and analyze the influence of some meteorological variables in the prediction. An emission episode is said to occur when the series of bi-hourly means of SO2 is greater than a specific level. For coal-fired power stations it is essential to predict emission epi- sodes sufficiently in advance so appropriate preventive measures can be taken. We proposed a meth- odology to predict SO2 emission episodes based on using an additive model and an algorithm for variable selection. The methodology was applied to the estimation of SO2 emissions registered in sampling lo- cations near a coal-fired power station located in Northern Spain. The results obtained indicate a good performance of the model considering only two terms of the time series and that the inclusion of the meteorological variables in the model is not significant.

A critical evaluation of methods for the reconstruction of tissue-specific models

Under the framework of constraint based modeling, genome-scale metabolic models (GSMMs) have been used for several tasks, such as metabolic engineering and phenotype prediction. More recently, their application in health related research has spanned drug discovery, biomarker identification and host-pathogen interactions, targeting diseases such as cancer, Alzheimer, obesity or diabetes. In the last years, the development of novel techniques for genome sequencing and other high-throughput methods, together with advances in Bioinformatics, allowed the reconstruction of GSMMs for human cells. Considering the diversity of cell types and tissues present in the human body, it is imperative to develop tissue-specific metabolic models. Methods to automatically generate these models, based on generic human metabolic models and a plethora of omics data, have been proposed. However, their results have not yet been adequately and critically evaluated and compared. This work presents a survey of the most important tissue or cell type specific metabolic model reconstruction methods, which use literature, transcriptomics, proteomics and metabolomics data, together with a global template model. As a case study, we analyzed the consistency between several omics data sources and reconstructed distinct metabolic models of hepatocytes using different methods and data sources as inputs. The results show that omics data sources have a poor overlapping and, in some cases, are even contradictory. Additionally, the hepatocyte metabolic models generated are in many cases not able to perform metabolic functions known to be present in the liver tissue. We conclude that reliable methods for a priori omics data integration are required to support the reconstruction of complex models of human cells.

Hazard assessment of storm events for the battery, New York

The environmental and socio-economic importance of coastal areas is widely recognized, but at present these areas face severe weaknesses and high-risk situations. The increased demand and growing human occupation of coastal zones have greatly contributed to exacerbating such weaknesses. Today, throughout the world, in all countries with coastal regions, episodes of waves overtopping and coastal flooding are frequent. These episodes are usually responsible for property losses and often put human lives at risk. The floods are caused by coastal storms primarily due to the action of very strong winds. The propagation of these storms towards the coast induces high water levels. It is expected that climate change phenomena will contribute to the intensification of coastal storms. In this context, an estimation of coastal flooding hazards is of paramount importance for the planning and management of coastal zones. Consequently, carrying out a series of storm scenarios and analyzing their impacts through numerical modeling is of prime interest to coastal decision-makers. Firstly, throughout this work, historical storm tracks and intensities are characterized for the northeastern region of United States coast, in terms of probability of occurrence. Secondly, several storm events with high potential of occurrence are generated using a specific tool of DelftDashboard interface for Delft3D software. Hydrodynamic models are then used to generate ensemble simulations to assess storms' effects on coastal water levels. For the United States’ northeastern coast, a highly refined regional domain is considered surrounding the area of The Battery, New York, situated in New York Harbor. Based on statistical data of numerical modeling results, a review of the impact of coastal storms to different locations within the study area is performed.

Introduction [to Contact force models for multibody dynamics]

"Series: Solid mechanics and its applications, vol. 226"

Pure elastic contact force models

"Series: Solid mechanics and its applications, vol. 226"

Dissipative contact force models

"Series: Solid mechanics and its applications, vol. 226"

Contact force models for multibody dynamics

"Series: Solid mechanics and its applications, vol. 226"

An evolutionary approach to the use of Petri net based models: from parallel controllers to HW/SW co-design

"A workshop within the 19th International Conference on Applications and Theory of Petri Nets - ICATPN’1998"

Hierarchical modelling of timber reference properties using probabilistic methods: Maximum Likelihood Method, Bayesian Methods and Probability Networks

In recent decades, an increased interest has been evidenced in the research on multi-scale hierarchical modelling in the field of mechanics, and also in the field of wood products and timber engineering. One of the main motivations for hierar-chical modelling is to understand how properties, composition and structure at lower scale levels may influence and be used to predict the material properties on a macroscopic and structural engineering scale. This chapter presents the applicability of statistic and probabilistic methods, such as the Maximum Likelihood method and Bayesian methods, in the representation of timber’s mechanical properties and its inference accounting to prior information obtained in different importance scales. These methods allow to analyse distinct timber’s reference properties, such as density, bending stiffness and strength, and hierarchically consider information obtained through different non, semi or destructive tests. The basis and fundaments of the methods are described and also recommendations and limitations are discussed. The methods may be used in several contexts, however require an expert’s knowledge to assess the correct statistic fitting and define the correlation arrangement between properties.

Real-Time models to predict the use of vasopressors in monitored patients

The needs of reducing human error has been growing in every field of study, and medicine is one of those. Through the implementation of technologies is possible to help in the decision making process of clinics, therefore to reduce the difficulties that are typically faced. This study focuses on easing some of those difficulties by presenting real-time data mining models capable of predicting if a monitored patient, typically admitted in intensive care, will need to take vasopressors. Data Mining models were induced using clinical variables such as vital signs, laboratory analysis, among others. The best model presented a sensitivity of 94.94%. With this model it is possible reducing the misuse of vasopressors acting as prevention. At same time it is offered a better care to patients by anticipating their treatment with vasopressors.

Real-Time decision support using data mining to predict blood pressure critical events in intensive medicine patients

Patient blood pressure is an important vital signal to the physicians take a decision and to better understand the patient condition. In Intensive Care Units is possible monitoring the blood pressure due the fact of the patient being in continuous monitoring through bedside monitors and the use of sensors. The intensivist only have access to vital signs values when they look to the monitor or consult the values hourly collected. Most important is the sequence of the values collected, i.e., a set of highest or lowest values can signify a critical event and bring future complications to a patient as is Hypotension or Hypertension. This complications can leverage a set of dangerous diseases and side-effects. The main goal of this work is to predict the probability of a patient has a blood pressure critical event in the next hours by combining a set of patient data collected in real-time and using Data Mining classification techniques. As output the models indicate the probability (%) of a patient has a Blood Pressure Critical Event in the next hour. The achieved results showed to be very promising, presenting sensitivity around of 95%.