In this paper we present a new multiple-pathway stochastic model of carcinogenesis with potential... more In this paper we present a new multiple-pathway stochastic model of carcinogenesis with potential of predicting individual incidence risks on the basis of biomedical measurements. The model incorporates the concept of intracellular barrier mechanisms in which cell malignization occurs due to an inefficient operation of barrier cell mechanisms, such as antioxidant defense, repair systems, and apoptosis. Mathematical formalism combines methodological innovations of mechanistic carcinogenesis models and stochastic process models widely used in studying biodemography of aging and longevity. An advantage of the modeling approach is in the natural combining of two types of measures expressed in terms of model parameters: age-specific hazard rate and means of barrier states. Results of simulation studies allow us to conclude that the model parameters can be estimated in joint analyses of epidemiological data and newly collected data on individual biomolecular measurements of barrier states...
In this paper we present a new multiple-pathway stochastic model of carcinogenesis with potential... more In this paper we present a new multiple-pathway stochastic model of carcinogenesis with potential of predicting individual incidence risks on the basis of biomedical measurements. The model incorporates the concept of intracellular barrier mechanisms in which cell malignization occurs due to an inefficient operation of barrier cell mechanisms, such as antioxidant defense, repair systems, and apoptosis. Mathematical formalism combines methodological innovations of mechanistic carcinogenesis models and stochastic process models widely used in studying biodemography of aging and longevity. An advantage of the modeling approach is in the natural combining of two types of measures expressed in terms of model parameters: age-specific hazard rate and means of barrier states. Results of simulation studies allow us to conclude that the model parameters can be estimated in joint analyses of epidemiological data and newly collected data on individual biomolecular measurements of barrier states...
We consider a scheme of aging with two possible mechanisms of senescence processes: aging with ap... more We consider a scheme of aging with two possible mechanisms of senescence processes: aging with apoptosis and necrosis for differentiated cells and a multistage process of malignant transformation. Our model describes the multistage phenomena of aging and carcinogenesis by a set of stochastic equations using multivariate and diffu-sion processes. This model fits experimental data on the acceleration of aging processes from postnatal exposure to 5-bromodeoxyuridine (BrdU), and the induction of genome instability. The methods of stochastic modeling and computer simulation of the processes of aging and carcinogenesis have been used for the verification of the biological suggestions. Introduction. The importance of experiments with 5-bromodeoxyuridine This work is devoted to investigation of accelerated aging and perspectives of theoretical and experimental
The multivariate survival distributions are used for description of dependent failure times (life... more The multivariate survival distributions are used for description of dependent failure times (life spans)
Adaptive trade-off in C. capitata is a characteristic feature of the long-lived subpopulation Max... more Adaptive trade-off in C. capitata is a characteristic feature of the long-lived subpopulation Max-Planck-Institut für demografi sche Forschung
Individuals differ in their susceptibility to various causes of morbidity and mortality. Epidemio... more Individuals differ in their susceptibility to various causes of morbidity and mortality. Epidemiologists are accustomed to thinking about this heterogeneity in terms of “risk factors” and “relative risks”. Some of the heterogeneity among individuals is genetic in origin and some is acquired as a result of individual behaviour (like cigarette smoking) or environmental exposure (to, say, water pollution). The levels of the risks faced by an individual change over time as the individual ages, changes his behaviour and is exposed to different conditions.
Riassunto L’obiettivo di questo lavoro è quello di analizzare la dinamica della mortalità per cau... more Riassunto L’obiettivo di questo lavoro è quello di analizzare la dinamica della mortalità per causa utilizzando un nuovo, semplice ed efficace strumento: la rappresentazione della principale causa di morte per età e nel tempo. Attraverso queste particolari superfici di mortalità, viene rivisitata la transizione epidemiologica in Italia. Focalizzando l’attenzione sull’ultima fase della transizione, vengono in seguito analizzati i più recenti profili della mortalità attraverso le superfici delle principali localizzazioni nell'ambito della classe dei tumori.
Hidden differences in the survival chances of individuals in a population influence the shape of ... more Hidden differences in the survival chances of individuals in a population influence the shape of the mortality rate observed in demographic and epidemiological studies. To evaluate the contribution of such hidden variations to observed hazards, frailty models have been suggested. The application of these models to the analysis of survival data in demography, epidemiology, and biostatistics has opened up new avenues for survival studies. However, along with many useful insights and ideas, several unjustified beliefs (myths) have also been generated. In this paper we critically discuss these beliefs. In particular, we discuss the notion of individual frailty and show that the interpretation thereof depends on the identifiability conditions specified for the respective frailty model. We discuss strengths and weaknesses of shared frailty models with and without observed covariates. We explain why bivariate correlated frailty models are the most appropriate for the analysis of survival d...
Variables measured in longitudinal studies of aging and longevity do not exhaust the list of all ... more Variables measured in longitudinal studies of aging and longevity do not exhaust the list of all factors affecting health and mortality transitions. Unobserved factors generate hidden variability in susceptibility to diseases and death in populations and in age trajectories of longitudinally measured indices. Effects of such heterogeneity can be manifested not only in observed hazard rates but also in average trajectories of measured indices. Although effects of hidden heterogeneity on observed mortality rates are widely discussed, their role in forming age patterns of other aging-related characteristics (average trajectories of physiological state, stress resistance, etc.) is less clear. We propose a model of hidden heterogeneity to analyze its effects in longitudinal data. The approach takes the presence of hidden heterogeneity into account and incorporates several major concepts currently developing in aging research (allostatic load, aging-associated decline in adaptive capacity...
Cancer is intimately connected with the intrinsic processes of ageing at several important levels... more Cancer is intimately connected with the intrinsic processes of ageing at several important levels. Firstly, incidence rates for the great majority of cancers rise steeply with advancing age. Secondly, there is an important overlap between the roles of molecular damage accumulation in ageing and cancer. Thirdly, there is a powerful inter-species correlation between longevity, rate of DNA repair and lifetime cancer risk. Fourthly, cancer and ageing are to some extent opposites in that ageing is associated with finite cell replication whereas cancer is associated with cell immortalisation. As evolutionary biologist Theodosius Dobzhansky observed: “Nothing in biology makes sense except in the light of evolution”. Cancer is a condition in which the role of natural selection needs to be understood not only in terms of the proximate mechanisms – how abnormal cells undergo intense cellular selection to proliferate and metastasise – but also in terms of the legacy of the processes that have ...
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no curative treatment a... more Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no curative treatment available. Exploring the genetic and non-genetic contributors to AD pathogenesis is essential to better understand its underlying biological mechanisms, and to develop novel preventive and therapeutic strategies. We investigated potential genetically driven epigenetic heterogeneity of AD through summary data-based Mendelian randomization (SMR), which combined results from our previous genome-wide association analyses with those from two publicly available methylation quantitative trait loci studies of blood and brain tissue samples. We found that 152 probes corresponding to 113 genes were epigenetically associated with AD at a Bonferroni-adjusted significance level of 5.49E-07. Of these, 10 genes had significant probes in both brain-specific and blood-based analyses. Comparing males vs. females and hypertensive vs. non-hypertensive subjects, we found that 22 and 79 probes had group-specif...
In this paper we present a new multiple-pathway stochastic model of carcinogenesis with potential... more In this paper we present a new multiple-pathway stochastic model of carcinogenesis with potential of predicting individual incidence risks on the basis of biomedical measurements. The model incorporates the concept of intracellular barrier mechanisms in which cell malignization occurs due to an inefficient operation of barrier cell mechanisms, such as antioxidant defense, repair systems, and apoptosis. Mathematical formalism combines methodological innovations of mechanistic carcinogenesis models and stochastic process models widely used in studying biodemography of aging and longevity. An advantage of the modeling approach is in the natural combining of two types of measures expressed in terms of model parameters: age-specific hazard rate and means of barrier states. Results of simulation studies allow us to conclude that the model parameters can be estimated in joint analyses of epidemiological data and newly collected data on individual biomolecular measurements of barrier states...
In this paper we present a new multiple-pathway stochastic model of carcinogenesis with potential... more In this paper we present a new multiple-pathway stochastic model of carcinogenesis with potential of predicting individual incidence risks on the basis of biomedical measurements. The model incorporates the concept of intracellular barrier mechanisms in which cell malignization occurs due to an inefficient operation of barrier cell mechanisms, such as antioxidant defense, repair systems, and apoptosis. Mathematical formalism combines methodological innovations of mechanistic carcinogenesis models and stochastic process models widely used in studying biodemography of aging and longevity. An advantage of the modeling approach is in the natural combining of two types of measures expressed in terms of model parameters: age-specific hazard rate and means of barrier states. Results of simulation studies allow us to conclude that the model parameters can be estimated in joint analyses of epidemiological data and newly collected data on individual biomolecular measurements of barrier states...
We consider a scheme of aging with two possible mechanisms of senescence processes: aging with ap... more We consider a scheme of aging with two possible mechanisms of senescence processes: aging with apoptosis and necrosis for differentiated cells and a multistage process of malignant transformation. Our model describes the multistage phenomena of aging and carcinogenesis by a set of stochastic equations using multivariate and diffu-sion processes. This model fits experimental data on the acceleration of aging processes from postnatal exposure to 5-bromodeoxyuridine (BrdU), and the induction of genome instability. The methods of stochastic modeling and computer simulation of the processes of aging and carcinogenesis have been used for the verification of the biological suggestions. Introduction. The importance of experiments with 5-bromodeoxyuridine This work is devoted to investigation of accelerated aging and perspectives of theoretical and experimental
The multivariate survival distributions are used for description of dependent failure times (life... more The multivariate survival distributions are used for description of dependent failure times (life spans)
Adaptive trade-off in C. capitata is a characteristic feature of the long-lived subpopulation Max... more Adaptive trade-off in C. capitata is a characteristic feature of the long-lived subpopulation Max-Planck-Institut für demografi sche Forschung
Individuals differ in their susceptibility to various causes of morbidity and mortality. Epidemio... more Individuals differ in their susceptibility to various causes of morbidity and mortality. Epidemiologists are accustomed to thinking about this heterogeneity in terms of “risk factors” and “relative risks”. Some of the heterogeneity among individuals is genetic in origin and some is acquired as a result of individual behaviour (like cigarette smoking) or environmental exposure (to, say, water pollution). The levels of the risks faced by an individual change over time as the individual ages, changes his behaviour and is exposed to different conditions.
Riassunto L’obiettivo di questo lavoro è quello di analizzare la dinamica della mortalità per cau... more Riassunto L’obiettivo di questo lavoro è quello di analizzare la dinamica della mortalità per causa utilizzando un nuovo, semplice ed efficace strumento: la rappresentazione della principale causa di morte per età e nel tempo. Attraverso queste particolari superfici di mortalità, viene rivisitata la transizione epidemiologica in Italia. Focalizzando l’attenzione sull’ultima fase della transizione, vengono in seguito analizzati i più recenti profili della mortalità attraverso le superfici delle principali localizzazioni nell'ambito della classe dei tumori.
Hidden differences in the survival chances of individuals in a population influence the shape of ... more Hidden differences in the survival chances of individuals in a population influence the shape of the mortality rate observed in demographic and epidemiological studies. To evaluate the contribution of such hidden variations to observed hazards, frailty models have been suggested. The application of these models to the analysis of survival data in demography, epidemiology, and biostatistics has opened up new avenues for survival studies. However, along with many useful insights and ideas, several unjustified beliefs (myths) have also been generated. In this paper we critically discuss these beliefs. In particular, we discuss the notion of individual frailty and show that the interpretation thereof depends on the identifiability conditions specified for the respective frailty model. We discuss strengths and weaknesses of shared frailty models with and without observed covariates. We explain why bivariate correlated frailty models are the most appropriate for the analysis of survival d...
Variables measured in longitudinal studies of aging and longevity do not exhaust the list of all ... more Variables measured in longitudinal studies of aging and longevity do not exhaust the list of all factors affecting health and mortality transitions. Unobserved factors generate hidden variability in susceptibility to diseases and death in populations and in age trajectories of longitudinally measured indices. Effects of such heterogeneity can be manifested not only in observed hazard rates but also in average trajectories of measured indices. Although effects of hidden heterogeneity on observed mortality rates are widely discussed, their role in forming age patterns of other aging-related characteristics (average trajectories of physiological state, stress resistance, etc.) is less clear. We propose a model of hidden heterogeneity to analyze its effects in longitudinal data. The approach takes the presence of hidden heterogeneity into account and incorporates several major concepts currently developing in aging research (allostatic load, aging-associated decline in adaptive capacity...
Cancer is intimately connected with the intrinsic processes of ageing at several important levels... more Cancer is intimately connected with the intrinsic processes of ageing at several important levels. Firstly, incidence rates for the great majority of cancers rise steeply with advancing age. Secondly, there is an important overlap between the roles of molecular damage accumulation in ageing and cancer. Thirdly, there is a powerful inter-species correlation between longevity, rate of DNA repair and lifetime cancer risk. Fourthly, cancer and ageing are to some extent opposites in that ageing is associated with finite cell replication whereas cancer is associated with cell immortalisation. As evolutionary biologist Theodosius Dobzhansky observed: “Nothing in biology makes sense except in the light of evolution”. Cancer is a condition in which the role of natural selection needs to be understood not only in terms of the proximate mechanisms – how abnormal cells undergo intense cellular selection to proliferate and metastasise – but also in terms of the legacy of the processes that have ...
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no curative treatment a... more Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no curative treatment available. Exploring the genetic and non-genetic contributors to AD pathogenesis is essential to better understand its underlying biological mechanisms, and to develop novel preventive and therapeutic strategies. We investigated potential genetically driven epigenetic heterogeneity of AD through summary data-based Mendelian randomization (SMR), which combined results from our previous genome-wide association analyses with those from two publicly available methylation quantitative trait loci studies of blood and brain tissue samples. We found that 152 probes corresponding to 113 genes were epigenetically associated with AD at a Bonferroni-adjusted significance level of 5.49E-07. Of these, 10 genes had significant probes in both brain-specific and blood-based analyses. Comparing males vs. females and hypertensive vs. non-hypertensive subjects, we found that 22 and 79 probes had group-specif...
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