Mathematical Modelling In Biomedicine

Mathematical modelling in biomedicine is a rapidly developing scientific discipline at the intersection of medicine, biology, mathematics, physics, and computer science. Its progress is stimulated by fundamental scientific questions and by the applications to public health. This book represents a collection of papers devoted to mathematical modelling of various physiological problems in normal and pathological conditions. It covers a broad range of topics including cardiovascular system and diseases, heart and brain modelling, tumor growth, viral infections, and immune response. Computational models of blood circulation are used to study the influence of heart arrhythmias on coronary blood flow and on operating modes for left-ventricle-assisted devices. Wave propagation in the cardiac tissue is investigated in order to show the influence of tissue heterogeneity and fibrosis. The models of tumor growth are used to determine optimal protocols of antiangiogenic and radiotherapy. The models of viral hepatitis kinetics are considered for the parameter identification, and the evolution of viral quasi-species is investigated. The book presents the state-of-the-art in mathematical modelling in biomedicine and opens new perspectives in this passionate field of research.

Mathematical biomedicine is a rapidly developing interdisciplinary field of research that connects the natural and exact sciences in an attempt to respond to the modeling and simulation challenges raised by biology and medicine. There exist a large number of mathematical methods and procedures that can be brought in to meet these challenges and this book presents a palette of such tools ranging from discrete cellular automata to cell population based models described by ordinary differential equations to nonlinear partial differential equations representing complex time- and space-dependent continuous processes. Both stochastic and deterministic methods are employed to analyze biological phenomena in various temporal and spatial settings. This book illustrates the breadth and depth of research opportunities that exist in the general field of mathematical biomedicine by highlighting some of the fascinating interactions that continue to develop between the mathematical and biomedical sciences. It consists of five parts that can be read independently, but are arranged to give the reader a broader picture of specific research topics and the mathematical tools that are being applied in its modeling and analysis. The main areas covered include immune system modeling, blood vessel dynamics, cancer modeling and treatment, and epidemiology. The chapters address topics that are at the forefront of current biomedical research such as cancer stem cells, immunodominance and viral epitopes, aggressive forms of brain cancer, or gene therapy. The presentations highlight how mathematical modeling can enhance biomedical understanding and will be of interest to both the mathematical and the biomedical communities including researchers already working in the field as well as those who might consider entering it. Much of the material is presented in a way that gives graduate students and young researchers a starting point for their own work.

Mathematical modelling in biomedicine is a rapidly developing scientific discipline at the intersection of medicine, biology, mathematics, physics, and computer science. Its progress is stimulated by fundamental scientific questions and by the applications to public health. This book represents a collection of papers devoted to mathematical modelling of various physiological problems in normal and pathological conditions. It covers a broad range of topics including cardiovascular system and diseases, heart and brain modelling, tumor growth, viral infections, and immune response. Computational models of blood circulation are used to study the influence of heart arrhythmias on coronary blood flow and on operating modes for left-ventricle-assisted devices. Wave propagation in the cardiac tissue is investigated in order to show the influence of tissue heterogeneity and fibrosis. The models of tumor growth are used to determine optimal protocols of antiangiogenic and radiotherapy. The models of viral hepatitis kinetics are considered for the parameter identification, and the evolution of viral quasi-species is investigated. The book presents the state-of-the-art in mathematical modelling in biomedicine and opens new perspectives in this passionate field of research.

The utilization of mathematical tools within biology and medicine has traditionally been less widespread compared to other hard sciences, such as physics and chemistry. However, an increased need for tools such as data processing, bioinformatics, statistics, and mathematical modeling, have emerged due to advancements during the last decades. These advancements are partly due to the development of high-throughput experimental procedures and techniques, which produce ever increasing amounts of data. For all aspects of biology and medicine, these data reveal a high level of inter-connectivity between components, which operate on many levels of control, and with multiple feedbacks both between and within each level of control. However, the availability of these large-scale data is not synonymous to a detailed mechanistic understanding of the underlying system. Rather, a mechanistic understanding is gained first when we construct a hypothesis, and test its predictions experimentally. Identifying interesting predictions that are quantitative in nature, generally requires mathematical modeling. This, in turn, requires that the studied system can be formulated into a mathematical model, such as a series of ordinary differential equations, where different hypotheses can be expressed as precise mathematical expressions that influence the output of the model. Within specific sub-domains of biology, the utilization of mathematical models have had a long tradition, such as the modeling done on electrophysiology by Hodgkin and Huxley in the 1950s. However, it is only in recent years, with the arrival of the field known as systems biology that mathematical modeling has become more commonplace. The somewhat slow adaptation of mathematical modeling in biology is partly due to historical differences in training and terminology, as well as in a lack of awareness of showcases illustrating how modeling can make a difference, or even be required, for a correct analysis of the experimental data. In this work, I provide such showcases by demonstrating the universality and applicability of mathematical modeling and hypothesis testing in three disparate biological systems. In Paper II, we demonstrate how mathematical modeling is necessary for the correct interpretation and analysis of dominant negative inhibition data in insulin signaling in primary human adipocytes. In Paper III, we use modeling to determine transport rates across the nuclear membrane in yeast cells, and we show how this technique is superior to traditional curve-fitting methods. We also demonstrate the issue of population heterogeneity and the need to account for individual differences between cells and the population at large. In Paper IV, we use mathematical modeling to reject three hypotheses concerning the phenomenon of facilitation in pyramidal nerve cells in rats and mice. We also show how one surviving hypothesis can explain all data and adequately describe independent validation data. Finally, in Paper I, we develop a method for model selection and discrimination using parametric bootstrapping and the combination of several different empirical distributions of traditional statistical tests. We show how the empirical log-likelihood ratio test is the best combination of two tests and how this can be used, not only for model selection, but also for model discrimination. In conclusion, mathematical modeling is a valuable tool for analyzing data and testing biological hypotheses, regardless of the underlying biological system. Further development of modeling methods and applications are therefore important since these will in all likelihood play a crucial role in all future aspects of biology and medicine, especially in dealing with the burden of increasing amounts of data that is made available with new experimental techniques. Användandet av matematiska verktyg har inom biologi och medicin traditionellt sett varit mindre utbredd jämfört med andra ämnen inom naturvetenskapen, såsom fysik och kemi. Ett ökat behov av verktyg som databehandling, bioinformatik, statistik och matematisk modellering har trätt fram tack vare framsteg under de senaste decennierna. Dessa framsteg är delvis ett resultat av utvecklingen av storskaliga datainsamlingstekniker. Inom alla områden av biologi och medicin så har dessa data avslöjat en hög nivå av interkonnektivitet mellan komponenter, verksamma på många kontrollnivåer och med flera återkopplingar både mellan och inom varje nivå av kontroll. Tillgång till storskaliga data är emellertid inte synonymt med en detaljerad mekanistisk förståelse för det underliggande systemet. Snarare uppnås en mekanisk förståelse först när vi bygger en hypotes vars prediktioner vi kan testa experimentellt. Att identifiera intressanta prediktioner som är av kvantitativ natur, kräver generellt sett matematisk modellering. Detta kräver i sin tur att det studerade systemet kan formuleras till en matematisk modell, såsom en serie ordinära differentialekvationer, där olika hypoteser kan uttryckas som precisa matematiska uttryck som påverkar modellens output. Inom vissa delområden av biologin har utnyttjandet av matematiska modeller haft en lång tradition, såsom den modellering gjord inom elektrofysiologi av Hodgkin och Huxley på 1950?talet. Det är emellertid just på senare år, med ankomsten av fältet systembiologi, som matematisk modellering har blivit ett vanligt inslag. Den något långsamma adapteringen av matematisk modellering inom biologi är bl.a. grundad i historiska skillnader i träning och terminologi, samt brist på medvetenhet om exempel som illustrerar hur modellering kan göra skillnad och faktiskt ofta är ett krav för en korrekt analys av experimentella data. I detta arbete tillhandahåller jag sådana exempel och demonstrerar den matematiska modelleringens och hypotestestningens allmängiltighet och tillämpbarhet i tre olika biologiska system. I Arbete II visar vi hur matematisk modellering är nödvändig för en korrekt tolkning och analys av dominant-negativ-inhiberingsdata vid insulinsignalering i primära humana adipocyter. I Arbete III använder vi modellering för att bestämma transporthastigheter över cellkärnmembranet i jästceller, och vi visar hur denna teknik är överlägsen traditionella kurvpassningsmetoder. Vi demonstrerar också frågan om populationsheterogenitet och behovet av att ta hänsyn till individuella skillnader mellan celler och befolkningen som helhet. I Arbete IV använder vi matematisk modellering för att förkasta tre hypoteser om hur fenomenet facilitering uppstår i pyramidala nervceller hos råttor och möss. Vi visar också hur en överlevande hypotes kan beskriva all data, inklusive oberoende valideringsdata. Slutligen utvecklar vi i Arbete I en metod för modellselektion och modelldiskriminering med hjälp av parametrisk ”bootstrapping” samt kombinationen av olika empiriska fördelningar av traditionella statistiska tester. Vi visar hur det empiriska ”log-likelihood-ratio-testet” är den bästa kombinationen av två tester och hur testet är applicerbart, inte bara för modellselektion, utan också för modelldiskriminering. Sammanfattningsvis är matematisk modellering ett värdefullt verktyg för att analysera data och testa biologiska hypoteser, oavsett underliggande biologiskt system. Vidare utveckling av modelleringsmetoder och tillämpningar är därför viktigt eftersom dessa sannolikt kommer att spela en avgörande roll i framtiden för biologi och medicin, särskilt när det gäller att hantera belastningen från ökande datamängder som blir tillgänglig med nya experimentella tekniker.

Mathematicalmodelingofhumanphysiopathologyisatremendouslyambitioustask. It encompasses the modeling of most diverse compartments such as the cardiovas- lar,respiratory,skeletalandnervoussystems,aswellasthemechanicalandbioch- ical interaction between blood ?ow and arterial walls, and electrocardiac processes and electric conduction in biological tissues. Mathematical models can be set up to simulate both vasculogenesis (the aggregation and organization of endothelial cells dispersed in a given environment) and angiogenesis (the formation of new vessels sprouting from an existing vessel) that are relevant to the formation of vascular networks, and in particular to the description of tumor growth. The integration of models aimed at simulating the cooperation and interrelation of different systems is an even more dif?cult task. It calls for the setting up of, for instance, interaction models for the integrated cardio-vascular system and the interplay between the central circulation and peripheral compartments, models for the mid-to-long range cardiovascular adjustments to pathological conditions (e.g., to account for surgical interventions, congenital malformations, or tumor growth), models for integration among circulation, tissue perfusion, biochemical and thermal regulation, models for parameter identi?cation and sensitivity analysis to parameter changes or data uncertainty – and many others.

This book on modelling and simulation in biomathematics will be invaluable to researchers who are interested in the emerging areas of the field. Graduate students in related areas as well as lecturers will also find it beneficial. Some of the chapters have been written by distinguished experts in the field. Sample Chapter(s). Chapter 1: Detecting Mosaic Structures in DNA Sequence Alignments (1,349 KB). Contents: Detecting Mosaic Structures in DNA Sequence Alignments (D Husmeier); Application of Statistical Methodology and Model Design to Socio-Behaviour of HIV Transmission (J Oluwoye); A Stochastic Model Incorporating HIV Treatments for a Heterosexual Population: Impact on Threshold Conditions (R J Gallop et al.); Modeling and Identification of the Dynamics of the MF-Influenced Free-Radical Transformations in Lipid-Modeling Substances and Lipids (J Bentsman et al.); Computer Simulation of Self-Reorganization in Biological Cells (D Greenspan); Modelling Biological Gel Contraction by Cells: Consequences of Cell Traction Forces Distribution and Initial Stress (S Ramtani); Peristaltic Transport of Physiological Fluids (J C Misra & S K Pandey); Mathematical Modelling of DNA Knots and Links (J C Misra & S Mukherjee); Using Monodomain Computer Models for the Simulation of Electric Fields During Excitation Spread in Cardiac Tissue (G Plank); Flow in Tubes with Complicated Geometries with Special Application to Blood Flow in Large Arteries (G Jayaraman); Mathematical Modeling in Reproductive Biomedicine (S Sharma & S K Guha); Image Theory and Applications in Bioelectromagnetics (P D Einziger et al.); Dynamics of Humanoid Robots: Geometrical and Topological Duality (V G Ivancevic); The Effects of Body Composition on Energy Expenditure and Weight Dynamics During Hypophagia: A Setpoint Analysis (F P Kozusko); Mathematical Models in Population Dynamics and Ecology (R Diluo); Modelling in Bone Biomechanics (J C Misra & S Samanta). Readership: Graduate students, academic and researchers in biomathematics, mathematical biology, mathematical modeling, biotechnology, biocomputing, biophysics, bioengineering and mechanics."