Decomposition of disparities in life expectancy with applications to administrative health claims and registry data.

Research shows that geographic disparities in life expectancy between leading and lagging states are increasing over time while racial disparities between Black and White Americans have been going down. In the 65+ age strata morbidity is the most common cause of death, making differences in morbidity and associated adverse health-related outcomes between advantaged and disadvantaged groups an important aspect of disparities in life expectancy at age 65 (LE65). In this study, we used Pollard's decomposition to evaluate the disease-related contributions to disparities in LE65 for two types of data with distinctly differing structures: population/registry and administrative claims. To do so, we analyzed Pollard's integral, which is exact by construction, and developed exact analytic solutions for both types of data without the need for numerical integration. The solutions are broadly applicable and easily implemented. Applying these solutions, we found that the largest relative contributions to geographic disparities in LE65 were chronic lower respiratory diseases, circulatory diseases, and lung cancer; and, to racial disparities: arterial hypertension, diabetes mellitus, and cerebrovascular diseases. Overall, the increase in LE65 observed over 1998-2005 and 2010-2017 was primarily due to a reduction in the contributions of acute and chronic ischemic diseases; this was partially offset by increased contributions of diseases of the nervous system including dementia and Alzheimer's disease.

Forecasting prevalence and mortality of Alzheimer's disease using the partitioning models.

OBJECTIVES: Health forecasting is an important aspect of ensuring that the health system can effectively respond to the changing epidemiological environment. Common models for forecasting Alzheimer's disease and related dementias (AD/ADRD) are based on simplifying methodological assumptions, applied to limited population subgroups, or do not allow analysis of medical interventions. This study uses 5 %-Medicare data (1991-2017) to identify, partition, and forecast age-adjusted prevalence and incidence-based mortality of AD as well as their causal components. METHODS: The core underlying methodology is the partitioning analysis that calculates the relative impact each component has on the overall trend as well as intertemporal changes in the strength and direction of these impacts. B-spline functions estimated for all parameters of partitioning models represent the basis for projections of these parameters in future. RESULTS: Prevalence of AD is predicted to be stable between 2017 and 2028 primarily due to a decline in the prevalence of pre-AD-diagnosis stroke. Mortality, on the other hand, is predicted to increase. In all cases the resulting patterns come from a trade-off of two disadvantageous processes: increased incidence and disimproved survival. Analysis of health interventions demonstrates that the projected burden of AD differs significantly and leads to alternative policy implications. DISCUSSION: We developed a forecasting model of AD/ADRD risks that involves rigorous mathematical models and incorporation of the dynamics of important determinative risk factors for AD/ADRD risk. The applications of such models for analyses of interventions would allow for predicting future burden of AD/ADRD conditional on a specific treatment regime.

Underlying mechanisms of change in cancer prevalence in older U.S. adults: contributions of incidence, survival, and ascertainment at early stages.

PURPOSE: To quantitatively evaluate contributions of trends in incidence, relative survival, and stage at diagnosis to the dynamics in the prevalence of major cancers (lung, prostate, colon, breast, urinary bladder, ovaries, stomach, pancreas, esophagus, kidney, liver, and skin melanoma) among older U.S. adults age 65 +. METHODS: Trend partitioning was applied to the Surveillance, Epidemiology, and End Results Program data for 1973-2016. RESULTS: Growth of cancer prevalence in older adults decelerated or even decreased over time for all studied cancers due to decreasing incidence and improving survival for most of cancers, with a smaller contribution of the stage at cancer diagnosis. Changes in the prevalence of cancers of the lung, colon, stomach, and breast were predominantly due to decreasing incidence, increasing survival and more frequent diagnoses at earlier stages. Changes in prevalence of some other cancers demonstrated adverse trends such as decreasing survival in localized and regional stages (urinary bladder and ovarian) and growing impact of late-stage diagnoses (esophageal cancer). CONCLUSION: While decelerating or decreasing prevalence of many cancers were due to a beneficial combination of decreasing incidence and increasing survival, there are cancers for which decelerating prevalence is due to lack of improvement in their stage-specific survival and/or increasing frequency of diagnosis at advanced stages. Overall, if the observed trends persist, it is likely that the burden associated with cancer prevalence in older U.S. adults will be lower  comparing to projections based on constant increasing prevalence have previously estimated.

A forecasting model of disease prevalence based on the McKendrick-von Foerster equation.

A new model for disease prevalence based on the analytical solutions of McKendric-von Foerster's partial differential equations is developed. Derivation of the model and methods to cross check obtained results are explicitly demonstrated. Obtained equations describe the time evolution of the healthy and unhealthy age-structured sub-populations and age patterns of disease prevalence. The projection of disease prevalence into the future requires estimates of time trends of age-specific disease incidence, relative survival functions, and prevalence at the initial age and year available in the data. The computational scheme for parameter estimations using Medicare data, analytical properties of the model, application for diabetes prevalence, and relationship with partitioning models are described and discussed. The model allows natural generalization for the case of several diseases as well as for modeling time trends in cause-specific mortality rates.

Theory of partitioning of disease prevalence and mortality in observational data.

In this study, we present a new theory of partitioning of disease prevalence and incidence-based mortality and demonstrate how this theory practically works for analyses of Medicare data. In the theory, the prevalence of a disease and incidence-based mortality are modeled in terms of disease incidence and survival after diagnosis supplemented by information on disease prevalence at the initial age and year available in a dataset. Partitioning of the trends of prevalence and mortality is calculated with minimal assumptions. The resulting expressions for the components of the trends are given by continuous functions of data. The estimator is consistent and stable. The developed methodology is applied for data on type 2 diabetes using individual records from a nationally representative 5% sample of Medicare beneficiaries age 65+. Numerical estimates show excellent concordance between empirical estimates and theoretical predictions. Evaluated partitioning model showed that both prevalence and mortality increase with time. The primary driving factors of the observed prevalence increase are improved survival and increased prevalence at age 65. The increase in diabetes-related mortality is driven by increased prevalence and unobserved trends in time-periods and age-groups outside of the range of the data used in the study. Finally, the properties of the new estimator, possible statistical and systematical uncertainties, and future practical applications of this methodology in epidemiology, demography, public health and health forecasting are discussed.

The quadratic hazard model for analyzing longitudinal data on aging, health, and the life span.

A better understanding of processes and mechanisms linking human aging with changes in health status and survival requires methods capable of analyzing new data that take into account knowledge about these processes accumulated in the field. In this paper, we describe an approach to analyses of longitudinal data based on the use of stochastic process models of human aging, health, and longevity which allows for incorporating state of the art advances in aging research into the model structure. In particular, the model incorporates the notions of resistance to stresses, adaptive capacity, and "optimal" (normal) physiological states. To capture the effects of exposure to persistent external disturbances, the notions of allostatic adaptation and allostatic load are introduced. These notions facilitate the description and explanation of deviations of individuals' physiological indices from their normal states, which increase the chances of disease development and death. The model provides a convenient conceptual framework for comprehensive systemic analyses of aging-related changes in humans using longitudinal data and linking these changes with genotyping profiles, morbidity, and mortality risks. The model is used for developing new statistical methods for analyzing longitudinal data on aging, health, and longevity.

Hormesis against aging and diseases: using properties of biological adaptation for health and survival improvement.

The idea of using hormesis for postponing aging and improving human health has been recently discussed in scientific literature. This paper shows that redundancy in renewal capacity, some portion of which become activated and manifested in hormesis effects, may originate as a result of interaction between living organisms and their environment. It is shown that such redundancy may normally exist for organisms in the wild, and not only in domesticated and laboratory animals. Further development of the hormesis idea requires: (i) investigating regularities of response to multiple stimuli; (ii) studying slow-time responses (e.g., physiological adaptation) to repeated stimuli; (iii) studying connection between slow and fast (e.g., developing at the cellular and sub-cellular levels) stress responses; (iv) translating knowledge accumulated in studies of animal model systems to humans; (v) evaluating unrealized potential for improving health and longevity using hormetic mechanisms. The use of mathematical and computer modeling for translating experimental knowledge about hormesis effects to humans, as well as connection between studying hormetic mechanisms and analyses of the age trajectories of physiological and biological indices affecting U-shapes curves of morbidity-mortality risks using longitudinal data on aging, health, and longevity are discussed.

[A model of resource reallocation during physiological adaptation in Mediterranean fruit fly females]. / Model' pereraspredeleniia resursa v khode fiziologicheskoi adaptatsii samok sredizemnomorskoi fruktovoi mukhi Ceratitis capitata.

Analysis of experimental data on longevity and fertility of females of Mediterranean fruit fly Ceratitis capitata demonstrates that flies lay fewer eggs on the average as the average life-span increases. At the same time, the values of individual life-span and the number of eggs laid are positively correlated. To explain these results, a resource model describing the allocation and reallocation of resources between two basic functions, reproduction and maintenance, was proposed. The reallocation of resources, is triggered by changes in environmental conditions such as diet changes, and the parameters of reallocation depend on the current environmental conditions. Modeling demonstrated that the results of experiments are greatly influenced by population selection and heterogeneity.

The impact of diet switching on resource allocation to reproduction and longevity in Mediterranean fruitflies.

Understanding the factors that determine the allocation and utilization of organism resources may provide an insight into the mechanisms of adaptation, ageing and reproduction. Resource allocation, which is regarded as a method of adaptation, increases fitness and is genetically controlled. Experiments with variable diet feeding of female Mediterranean fruitflies (Ceratitis capitata) demonstrated that the feeding regime dramatically influences lifespan, mortality and the reproduction of flies. An analysis of experimental data and numerical experiments reveals that resource allocation could explain lifespan increase when females are switched from a sugar-only to a protein-containing diet. The heterogeneity of the initial female cohort in terms of the total amount of resources and its allocation to the processes of maintenance and reproduction plays a significant role in this.

How an individual fecundity pattern looks in Drosophila and medflies.

Reproduction usually is characterized by a mean-population fecundity pattern. Such a pattern has a maximum at earlier ages and a subsequent gradual decline in egg production. It is shown that individual fecundity trajectories do not follow such a pattern. In particular, the regular individual fecundity pattern has no maximum so that experimentally observed maximums are average-related artifacts. The three-stage description of individual fecundity, which includes maturation, maturity, and reproductive senescence, is more appropriate. Data are presented for Drosophila and Mediterranean fruitfly females that clearly confirm this hypothesis. A systematic error between egg-laying scores and the regular individual pattern allows for evaluation of how close the random scores are to the pattern. The first finding of the analysis of the systematic errors is that they are consistent with the three-stage hypothesis and do not contradict the absence of the maximum in the regular individual pattern. The other finding is the existence of obvious dynamic properties of the systematic error. The slow decrease in egg-laying at the maturity stage might be the result of a cost of mating. It can also be a consequence of "structural" senescence, that is, a slow rate accumulation of oxidative damage in the gonads.

Assessing genetic association with human survival at multi-allelic loci.

Genetic variation plays an important role in natural selection and population evolution. However, it also presents geneticists interested in aging research with problems in data analysis because of the large number of alleles and their various modes of action. Recently, a new statistical method based on survival analysis (the relative risk model or the RR model) has been introduced to assess gene-longevity associations [Yashin et al. (1999) Am J Hum Genet 65: 1178-1193] which outperforms the traditional gene frequency method. Here we extend the model to deal with polymorphic genes or gene markers. Assuming the Hardy-Weinberg equilibrium at birth, we first introduce an allele-based parameterization on gene frequency which helps to cut down the number of frequency parameters to be estimated. We then propose both the genotype and allele-based parameterizations on risk parameters to estimate genotype and allelic relative risks (the GRR and ARR models). While the GRR model allows us to investigate whether the alleles are recessive, dominant or codominant, the ARR model further minimizes the number of parameters to be estimated. As an example, we apply the methods to empirical data on Renin gene polymorphism and longevity. We show that our models can serve as useful tools in searching for important genetic variations implicated in human aging and longevity.

Systemic mechanisms of individual reproductive life history in female Medflies.

This paper is the second one in a series of two papers hypothesizing and testing systemic grounds of reproductive life history in the female fruit fly. In the first paper, we analyzed mechanisms of individual fecundity scheduling and have drawn the following conclusions. Individual fecundity in female flies is endowed as a flat pattern with a steady-state period of a constant rate of egg-laying. An individual female reveals three stages in her adult life history: maturation, maturity, and senescence. The first stage is a transient period of achieving a steady state at maturity, which can be maintained until the senescence stage. Thus, an individual fecundity pattern has no maximum. The maximums observed experimentally are averaging-caused artifacts. Two natural causes of deaths exist in flies, senescence-caused ones and premature deaths, probably due to a reproductive overload. In this paper, to confirm these findings, we use individual daily scores of egg-laying in four populations of Mediterranean fruit flies. Based on fecundity scores, we divide each Medfly population into four classes, namely zero-egg, short-, medium- and long-lived egg-layers. We demonstrate that, indeed, the three above findings definitely exist in Medflies. Our procedure allows the efficient storage of individual fecundity in parametric form, with only five numbers for each fly. Finally, this protocol will allow a more precise analysis of fecundity-energy trade-offs in flies carrying appropriate longevity mutations.

Logistic regression models for polymorphic and antagonistic pleiotropic gene action on human aging and longevity.

In this paper, we apply logistic regression models to measure genetic association with human survival for highly polymorphic and pleiotropic genes. By modelling genotype frequency as a function of age, we introduce a logistic regression model with polytomous responses to handle the polymorphic situation. Genotype and allele-based parameterization can be used to investigate the modes of gene action and to reduce the number of parameters, so that the power is increased while the amount of multiple testing minimized. A binomial logistic regression model with fractional polynomials is used to capture the age-dependent or antagonistic pleiotropic effects. The models are applied to HFE genotype data to assess the effects on human longevity by different alleles and to detect if an age-dependent effect exists. Application has shown that these methods can serve as useful tools in searching for important gene variations that contribute to human aging and longevity.

Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly.

The human sirtuin 3 (SIRT3) gene encodes a putative mitochondrial NAD-dependent deacetylase (SIRT3) which belongs to the evolutionary conserved family of sirtuin 2 proteins. Studies in model organisms have demonstrated that SIR2 genes control lifespan, while no data are available regarding a possible role of SIRT3 in human longevity. By analysing the genotype-specific survival function relevant to the G477T marker of SIRT3, we found that in males the TT genotype increases (p=0.0272), while the GT genotype decreases (p=0.0391) survival in the elderly. Since SIRT3 lies in a chromosomal region (11p15.5) where four genes potentially associated with longevity are located (HRAS1, Insulin-like Growth Factor 2, Proinsulin, and Tyrosine Hydroxylase) we tested for linkage-disequilibrium between G477T alleles and alleles of the above genes. The disequilibrium was not significant in any case, thus suggesting that SIRT3 itself, or a gene strictly linked to SIRT3, may have a role in human longevity.

How the analysis of genetic mutations can help us to solve basic problems in gerontology? I. Life extending genetic modifications in round worm C. elegans.

The results of recent molecular biological studies of aging and longevity confirmed substantial genetic contribution to the life span. The analysis of these findings showed substantial role of specific mutations in genes involved in regulatory processes on both the extra- and intracellular levels. We suggest that difference in responses of intact and mutant animals to the same set of environmental signals may be useful to clarify contribution of organism-environment interactions into the rate of aging, mortality and longevity of respective organisms. In our opinion such clarification is important for better understanding the origin of natural senescence and its dependence on external conditions.

What does a fly's individual fecundity pattern look like? The dynamics of resource allocation in reproduction and ageing.

Reproduction is usually characterised by an average fecundity pattern having a maximum at earlier ages and a subsequent gradual decline later on. An individual fecundity trajectory does not follow such a pattern and has no maximum. A three-stage pattern, which includes maturation, maturity and reproductive senescence, is a more appropriate description. An analysis of the power balance of an adult female fly during its life course allows us to predict two critical periods in an individual life history. The first crisis occurs at early ages when the increasing power demand becomes greater than the power supply. It often results in premature death. The surviving flies enjoy maturity and lay eggs at a presumably constant rate. The second critical period at advanced ages ends up in a senescence-caused death. Our approach predicts that there will be a bimodal death time distribution for a population of flies.

How the analysis of genetic mutations can help us to solve basic problems in gerontology? II. Life extending genetic modifications in budding yeast S. cereviseae, fruit fly D. melanogaster and laboratory mice M. musculus.

Most studies of aging are conducted in humans and domestic or laboratory animals, i.e. in conditions where artificial environment protection is applied, This yields changes in physiology and behavior, which set up organism's state unobserved in wild life. This state may be less adequate to the evolutionary adjusted genetic construction of an organism, which generates a hypothesis that in natural niches the aging rate can be lower and stress resistance can be higher than in captivity despite the fact that life expectancy in habitat is essentially lower than that in laboratory conditions due to high external mortality. Direct test of this hypothesis is difficult because of problems related to reconstruction of natural environment conditions in the laboratory. Substantial life-extending effect of some mutated genes can serve as indirect test of the hypothesis. We propose that in some cases genetic mutations can distort reaction of an organism on environmental cues and change control parameters of its life cycle. As a result such mutants in laboratory may partly demonstrate life traits similar to those observed in natural environment, e.g. associated with high stress resistance and low rate of aging. These features combined with low external mortality in laboratory conditions may lead to significant extension in the life span of mutants. Recently we considered 56 life-extending gene modifications in nematode C. elegans (Adv. Gerontol., 2003, Vol. 11), scattered in many publications. In this paper we consider pertinent life-extending gene modifications corresponded to the budding yeast S. cerevisease (29 genes), fruit fly D. melanogaster (22 genes) and laboratory mice M. musculus (8 genes).

Effect of neuronol on lifespan and development of spontaneous tumors in SAMP-1 mice with genetically accelerated aging.

Treatment of female SAMP-1 mice with Neuronol (drug containing succinic acid) given with drinking water starting from the age of 2 months during the whole life prolonged the lifespan and markedly reduced mortality of animals aged 1.5-2 years. Neuronol inhibited the development of spontaneous tumors, primarily lymphomas, and significantly prolonged lifespan in mice with tumors. Long-term treatment with Neuronol had no pathological side effects. Our experiments demonstrated geroprotective and anticarcinogenic activity of Neuronol and safety of its long-term use.

Male/female ratio in centenarians: a possible role played by population genetic structure.

All the demographic surveys on the centenarians have highlighted that females outnumber males. The centenarians' male/female (M/F) ratio reported by most studies ranges between 1:4 and 1:7. A puzzling 1:2 ratio was observed in Calabria, a Southern Italian region. To our knowledge only in Sardinia a similar phenomenon had been previously observed. We have therefore used the data of the Italian Institute of Statistics to figure out the centenarians' M/F ratio in the Italian regions. We found that this ratio gradually decreases from South to North. Such a result is certainly due to many factors. Thus, we have explored the possibility, it is also influenced by the genetic structure of the Italian population. In fact, the distribution of the centenarians' M/F ratio turned out to be significantly correlated with the genetic structure of the Italian population as outlined by the principal component analysis.

Epithalon decelerates aging and suppresses development of breast adenocarcinomas in transgenic her-2/neu mice.

Female transgenic FVB/N mice carrying the breast cancer gene HER-2/neu received epithalon (Ala-Glu-Asp-Gly) in a dose of 1 mg subcutaneously 5 times a week to from the 2nd month of life to death. Epithalon prolonged the average and maximum lifetimes of mice by 13.5 (p<0.05) and 13.9%, respectively. The peptide prolonged the average lifetime of animals without neoplasms (by 34.2%, p<0.05). Epithalon decelerated the development of age-related disturbances in reproductive activity and suppressed the formation of neoplasms. The peptide decreased the incidence of breast adenocarcinomas, lungs metastases (by 1.6 times, p<0.05), and multiple tumors (by 2 times). Epithalon 3.7-fold increased the number of mice without breast tumors (p<0.05), while the number of animals with 6 or more breast tumors decreased by 3 times (p<0.05). Epithalon prolonged the lifetime of mice with breast tumors by 1.4 times (p<0.05). These results indicate that Epithalon possesses geroprotective activity and inhibits breast carcinogenesis in transgenic mice, which is probably related to suppression of HER-2/neu expression.