Browsing by Author "Stallard, Eric"
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Item Open Access A new algorithm for predicting time to disease endpoints in Alzheimer's disease patients.(J Alzheimers Dis, 2014) Razlighi, Qolamreza R; Stallard, Eric; Brandt, Jason; Blacker, Deborah; Albert, Marilyn; Scarmeas, Nikolaos; Kinosian, Bruce; Yashin, Anatoliy I; Stern, YaakovBACKGROUND: The ability to predict the length of time to death and institutionalization has strong implications for Alzheimer's disease patients and caregivers, health policy, economics, and the design of intervention studies. OBJECTIVE: To develop and validate a prediction algorithm that uses data from a single visit to estimate time to important disease endpoints for individual Alzheimer's disease patients. METHOD: Two separate study cohorts (Predictors 1, N = 252; Predictors 2, N = 254), all initially with mild Alzheimer's disease, were followed for 10 years at three research centers with semiannual assessments that included cognition, functional capacity, and medical, psychiatric, and neurologic information. The prediction algorithm was based on a longitudinal Grade of Membership model developed using the complete series of semiannually-collected Predictors 1 data. The algorithm was validated on the Predictors 2 data using data only from the initial assessment to predict separate survival curves for three outcomes. RESULTS: For each of the three outcome measures, the predicted survival curves fell well within the 95% confidence intervals of the observed survival curves. Patients were also divided into quintiles for each endpoint to assess the calibration of the algorithm for extreme patient profiles. In all cases, the actual and predicted survival curves were statistically equivalent. Predictive accuracy was maintained even when key baseline variables were excluded, demonstrating the high resilience of the algorithm to missing data. CONCLUSION: The new prediction algorithm accurately predicts time to death, institutionalization, and need for full-time care in individual Alzheimer's disease patients; it can be readily adapted to predict other important disease endpoints. The algorithm will serve an unmet clinical, research, and public health need.Item Open Access Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan.(PLoS Genet, 2014-01) Kulminski, Alexander M; Arbeev, Konstantin G; Culminskaya, Irina; Arbeeva, Liubov; Ukraintseva, Svetlana V; Stallard, Eric; Christensen, Kaare; Schupf, Nicole; Province, Michael A; Yashin, Anatoli IEnduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The analyses show that women's lifespan is more sensitive to the e4 allele than men's in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LLFS with relative risk of death RR = 1.48 (p = 3.6 × 10(-6)) in the FHS cohorts. Major human diseases including CVD, ND, and cancer, whose risks can be sensitive to the e4 allele, do not mediate the association of this allele with lifespan in large FHS samples. Non-skin cancer non-additively increases mortality of the FHS women with moderate lifespans increasing the risks of death of the e4 carriers with cancer two-fold compared to the non-e4 carriers, i.e., RR = 2.07 (p = 5.0 × 10(-7)). The results suggest a pivotal role of non-sex-specific cancer as a nonlinear modulator of survival in this sample that increases the risk of death of the ApoE4 carriers by 150% (p = 5.3 × 10(-8)) compared to the non-carriers. This risk explains the 4.2 year shorter life expectancy of the e4 carriers compared to the non-carriers in this sample. The analyses suggest the existence of age- and gender-sensitive systemic mechanisms linking the e4 allele to lifespan which can non-additively interfere with cancer-related mechanisms.Item Open Access Biogenetic mechanisms predisposing to complex phenotypes in parents may function differently in their children.(J Gerontol A Biol Sci Med Sci, 2013-07) Kulminski, Alexander M; Arbeev, Konstantin G; Christensen, Kaare; Stallard, Eric; Miljkovic, Iva; Barmada, Michael; Yashin, Anatoliy IThis study focuses on the participants of the Long Life Family Study to elucidate whether biogenetic mechanisms underlying relationships among heritable complex phenotypes in parents function in the same way for the same phenotypes in their children. Our results reveal 3 characteristic groups of relationships among phenotypes in parents and children. One group composed of 3 pairs of phenotypes confirms that associations among some phenotypes can be explained by the same biogenetic mechanisms working in parents and children. Two other groups including 9 phenotype pairs show that this is not a common rule. Our findings suggest that biogenetic mechanisms underlying relationships among different phenotypes, even if they are causally related, can function differently in successive generations or in different age groups of biologically related individuals. The results suggest that the role of aging-related processes in changing environment may be conceptually underestimated in current genetic association studies using genome wide resources.Item Open Access Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies.(PLoS One, 2015) Kulminski, Alexander M; Culminskaya, Irina; Arbeev, Konstantin G; Arbeeva, Liubov; Ukraintseva, Svetlana V; Stallard, Eric; Wu, Deqing; Yashin, Anatoliy IInsights into genetic origin of diseases and related traits could substantially impact strategies for improving human health. The results of genome-wide association studies (GWAS) are often positioned as discoveries of unconditional risk alleles of complex health traits. We re-analyzed the associations of single nucleotide polymorphisms (SNPs) associated with total cholesterol (TC) in a large-scale GWAS meta-analysis. We focused on three generations of genotyped participants of the Framingham Heart Study (FHS). We show that the effects of all ten directly-genotyped SNPs were clustered in different FHS generations and/or birth cohorts in a sex-specific or sex-unspecific manner. The sample size and procedure-therapeutic issues play, at most, a minor role in this clustering. An important result was clustering of significant associations with the strongest effects in the youngest, or 3rd Generation, cohort. These results imply that an assumption of unconditional connections of these SNPs with TC is generally implausible and that a demographic perspective can substantially improve GWAS efficiency. The analyses of genetic effects in age-matched samples suggest a role of environmental and age-related mechanisms in the associations of different SNPs with TC. Analysis of the literature supports systemic roles for genes for these SNPs beyond those related to lipid metabolism. Our analyses reveal strong antagonistic effects of rs2479409 (the PCSK9 gene) that cautions strategies aimed at targeting this gene in the next generation of lipid drugs. Our results suggest that standard GWAS strategies need to be advanced in order to appropriately address the problem of genetic susceptibility to complex traits that is imperative for translation to health care.Item Open Access Does Medicaid pay more to a program of all-inclusive care for the elderly (PACE) than for fee-for-service long-term care?(J Gerontol A Biol Sci Med Sci, 2013-01) Wieland, Darryl; Kinosian, Bruce; Stallard, Eric; Boland, RebeccaBACKGROUND: In rebalancing from nursing homes (NHs), states are increasing access of NH-certified dually eligible (Medicare/Medicaid) patients to community waiver programs and Programs of All-Inclusive Care for the Elderly (PACE). Prior evaluations suggest Medicaid's PACE capitation exceeds its spending for comparable admissions in alternative care, although the latter may be underestimated. We test whether Medicaid payments to PACE are lower than predicted fee-for-service outlays in a long-term care admission cohort. METHODS: Using grade-of-membership methods, we model health deficits for dual eligibles aged 55 or more entering waiver, PACE, and NH in South Carolina (n = 3,988). Clinical types, membership vectors, and program type prevalences are estimated. We calculate a blend, fitting PACE between fee-for-service cohorts, whose postadmission 1-year utilization was converted to attrition-adjusted outlays. PACE's capitation is compared with blend-based expenditure predictions. RESULTS: Four clinical types describe population health deficits/service needs. The waiver cohort is most represented in the least impaired type (1: 47.1%), NH entrants in the most disabled (4: 38.5%). Most prevalent in PACE was a dementia type, 3 (32.7%). PACE's blend was waiver: 0.5602 (95% CI: 0.5472, 0.5732) and NH: 0.4398 (0.4268, 0.4528). Average Medicaid attrition-adjusted 1-year payments for waiver and NH were $4,177 and $77,945. The mean predicted cost for PACE patients in alternative long-term care was $36,620 ($35,662 and $37,580). PACE's Medicaid capitation was $27,648-28% below the lower limit of predicted fee-for-service payments. CONCLUSIONS: PACE's capitation was well under outlays for equivalent patients in alternative care-a substantial savings for Medicaid. Our methods provide a rate-setting element for PACE and other managed long-term care.Item Open Access Estimation and validation of a multiattribute model of Alzheimer disease progression.(Med Decis Making, 2010-11) Stallard, Eric; Kinosian, Bruce; Zbrozek, Arthur S; Yashin, Anatoliy I; Glick, Henry A; Stern, YaakovOBJECTIVES: To estimate and validate a multiattribute model of the clinical course of Alzheimer disease (AD) from mild AD to death in a high-quality prospective cohort study, and to estimate the impact of hypothetical modifications to AD progression rates on costs associated with Medicare and Medicaid services. DATA AND METHODS: The authors estimated sex-specific longitudinal Grade of Membership (GoM) models for AD patients (103 men, 149 women) in the initial cohort of the Predictors Study (1989-2001) based on 80 individual measures obtained every 6 mo for 10 y. These models were replicated for AD patients (106 men, 148 women) in the 2nd Predictors Study cohort (1997-2007). Model validation required that the disease-specific transition parameters be identical for both Predictors Study cohorts. Medicare costs were estimated from the National Long Term Care Survey. RESULTS: Sex-specific models were validated using the 2nd Predictors Study cohort with the GoM transition parameters constrained to the values estimated for the 1st Predictors Study cohort; 57 to 61 of the 80 individual measures contributed significantly to the GoM models. Simulated, cost-free interventions in the rate of progression of AD indicated that large potential cost offsets could occur for patients at the earliest stages of AD. CONCLUSIONS: AD progression is characterized by a small number of parameters governing changes in large numbers of correlated indicators of AD severity. The analysis confirmed that the progression of AD represents a complex multidimensional physiological process that is similar across different study cohorts. The estimates suggested that there could be large cost offsets to Medicare and Medicaid from the slowing of AD progression among patients with mild AD. The methodology appears generally applicable in AD modeling.Item Open Access Explicating heterogeneity of complex traits has strong potential for improving GWAS efficiency.(Sci Rep, 2016-10-14) Kulminski, Alexander M; Loika, Yury; Culminskaya, Irina; Arbeev, Konstantin G; Ukraintseva, Svetlana V; Stallard, Eric; Yashin, Anatoliy ICommon strategy of genome-wide association studies (GWAS) relying on large samples faces difficulties, which raise concerns that GWAS have exhausted their potential, particularly for complex traits. Here, we examine the efficiency of the traditional sample-size-centered strategy in GWAS of these traits, and its potential for improvement. The paper focuses on the results of the four largest GWAS meta-analyses of body mass index (BMI) and lipids. We show that just increasing sample size may not make p-values of genetic effects in large (N > 100,000) samples smaller but can make them larger. The efficiency of these GWAS, defined as ratio of the log-transformed p-value to the sample size, in larger samples was larger than in smaller samples for a small fraction of loci. These results emphasize the important role of heterogeneity in genetic associations with complex traits such as BMI and lipids. They highlight the substantial potential for improving GWAS by explicating this role (affecting 11-79% of loci in the selected GWAS), especially the effects of biodemographic processes, which are heavily underexplored in current GWAS and which are important sources of heterogeneity in the various study populations. Further progress in this direction is crucial for efficient use of genetic discoveries in health care.Item Open Access Genetic Structures of Population Cohorts Change with Increasing Age: Implications for Genetic Analyses of Human aging and Life Span.(Ann Gerontol Geriatr Res, 2017-06-02) Yashin, Anatoliy I; Wu, Deqing; Arbeev, Konstantin G; Arbeeva, Liubov S; Akushevich, Igor; Kulminski, Alexander; Culminskaya, Irina; Stallard, Eric; Ukraintseva, Svetlana VBACKGROUND: Correcting for the potential effects of population stratification is an important issue in genome wide association studies (GWAS) of complex traits. Principal component analysis (PCA) of the genetic structure of the population under study with subsequent incorporation of the first several principal components (PCs) in the GWAS regression model is often used for this purpose. PROBLEM: For longevity related traits such a correction may negatively affect the accuracy of genetic analyses. This is because PCs may capture genetic structure induced by mortality selection processes in genetically heterogeneous populations. DATA AND METHODS: We used the Framingham Heart Study data on life span and on individual genetic background to construct two sets of PCs. One was constructed to separate population stratification due to differences in ancestry from that induced by mortality selection. The other was constructed using genetic data on individuals of different ages without attempting to separate the ancestry effects from the mortality selection effects. The GWASs of human life span were performed using the first 20 PCs from each of the selected sets to control for possible population stratification. RESULTS: The results indicated that the GWAS that used the PC set separating population stratification induced by mortality selection from differences in ancestry produced stronger genetic signals than the GWAS that used PCs without such separation. CONCLUSION: The quality of genetic estimates in GWAS can be improved when changes in genetic structure caused by mortality selection are taken into account in controlling for possible effects of population stratification.Item Open Access Genetics of aging, health, and survival: dynamic regulation of human longevity related traits.(Front Genet, 2015) Yashin, Anatoliy I; Wu, Deqing; Arbeeva, Liubov S; Arbeev, Konstantin G; Kulminski, Alexander M; Akushevich, Igor; Kovtun, Mikhail; Culminskaya, Irina; Stallard, Eric; Li, Miaozhu; Ukraintseva, Svetlana VBACKGROUND: The roles of genetic factors in human longevity would be better understood if one can use more efficient methods in genetic analyses and investigate pleiotropic effects of genetic variants on aging and health related traits. DATA AND METHODS: We used EMMAX software with modified correction for population stratification to perform genome wide association studies (GWAS) of female lifespan from the original FHS cohort. The male data from the original FHS cohort and male and female data combined from the offspring FHS cohort were used to confirm findings. We evaluated pleiotropic effects of selected genetic variants as well as gene-smoking interactions on health and aging related traits. Then we reviewed current knowledge on functional properties of genes related to detected variants. RESULTS: The eight SNPs with genome-wide significant variants were negatively associated with lifespan in both males and females. After additional QC, two of these variants were selected for further analyses of their associations with major diseases (cancer and CHD) and physiological aging changes. Gene-smoking interactions contributed to these effects. Genes closest to detected variants appear to be involved in similar biological processes and health disorders, as those found in other studies of aging and longevity e.g., in cancer and neurodegeneration. CONCLUSIONS: The impact of genes on longevity may involve trade-off-like effects on different health traits. Genes that influence lifespan represent various molecular functions but may be involved in similar biological processes and health disorders, which could contribute to genetic heterogeneity of longevity and the lack of replication in genetic association studies.Item Open Access How genes influence life span: the biodemography of human survival.(Rejuvenation Res, 2012-08) Yashin, Anatoliy I; Wu, Deqing; Arbeev, Konstantin G; Stallard, Eric; Land, Kenneth C; Ukraintseva, Svetlana VBACKGROUND: In genome-wide association studies (GWAS) of human life span, none of the genetic variants has reached the level of genome-wide statistical significance. The roles of such variants in life span regulation remain unclear. DATA AND METHOD: A biodemographic analyses was done of genetic regulation of life span using data on low-significance longevity alleles selected in the earlier GWAS of the original Framingham cohort. RESULTS: Age-specific survival curves considered as functions of the number of longevity alleles exhibit regularities known in demography as "rectangularization" of survival curves. The presence of such pattern confirms observations from experimental studies that regulation of life span involves genes responsible for stress resistance. CONCLUSION: Biodemographic analyses could provide important information about the properties of genes affecting phenotypic traits.Item Open Access How lifespan associated genes modulate aging changes: lessons from analysis of longitudinal data.(Front Genet, 2013) Yashin, Anatoliy I; Arbeev, Konstantin G; Wu, Deqing; Arbeeva, Liubov S; Kulminski, Alexander; Akushevich, Igor; Culminskaya, Irina; Stallard, Eric; Ukraintseva, Svetlana VBACKGROUND AND OBJECTIVE: The influence of genes on human lifespan is mediated by biological processes that characterize body's functioning. The age trajectories of these processes contain important information about mechanisms linking aging, health, and lifespan. The objective of this paper is to investigate regularities of aging changes in different groups of individuals, including individuals with different genetic background, as well as their connections with health and lifespan. DATA AND METHOD: To reach this objective we used longitudinal data on four physiological variables, information about health and lifespan collected in the Framingham Heart Study (FHS), data on longevity alleles detected in earlier study, as well as methods of statistical modeling. RESULTS: We found that phenotypes of exceptional longevity and health are linked to distinct types of changes in physiological indices during aging. We also found that components of aging changes differ in groups of individuals with different genetic background. CONCLUSIONS: These results suggest that factors responsible for exceptional longevity and health are not necessary the same, and that postponing aging changes is associated with extreme longevity. The genetic factors which increase lifespan are associated with physiological changes typical of healthy and long-living individuals, smaller mortality risks from cancer and CVD and better estimates of adaptive capacity in statistical modeling. This indicates that extreme longevity and health related traits are likely to be less heterogeneous phenotypes than lifespan, and studying these phenotypes separately from lifespan may provide additional information about mechanisms of human aging and its relation to chronic diseases and lifespan.Item Open Access How the effects of aging and stresses of life are integrated in mortality rates: insights for genetic studies of human health and longevity.(Biogerontology, 2016-02) Yashin, Anatoliy I; Arbeev, Konstantin G; Arbeeva, Liubov S; Wu, Deqing; Akushevich, Igor; Kovtun, Mikhail; Yashkin, Arseniy; Kulminski, Alexander; Culminskaya, Irina; Stallard, Eric; Li, Miaozhu; Ukraintseva, Svetlana VIncreasing proportions of elderly individuals in developed countries combined with substantial increases in related medical expenditures make the improvement of the health of the elderly a high priority today. If the process of aging by individuals is a major cause of age related health declines then postponing aging could be an efficient strategy for improving the health of the elderly. Implementing this strategy requires a better understanding of genetic and non-genetic connections among aging, health, and longevity. We review progress and problems in research areas whose development may contribute to analyses of such connections. These include genetic studies of human aging and longevity, the heterogeneity of populations with respect to their susceptibility to disease and death, forces that shape age patterns of human mortality, secular trends in mortality decline, and integrative mortality modeling using longitudinal data. The dynamic involvement of genetic factors in (i) morbidity/mortality risks, (ii) responses to stresses of life, (iii) multi-morbidities of many elderly individuals, (iv) trade-offs for diseases, (v) genetic heterogeneity, and (vi) other relevant aging-related health declines, underscores the need for a comprehensive, integrated approach to analyze the genetic connections for all of the above aspects of aging-related changes. The dynamic relationships among aging, health, and longevity traits would be better understood if one linked several research fields within one conceptual framework that allowed for efficient analyses of available longitudinal data using the wealth of available knowledge about aging, health, and longevity already accumulated in the research field.Item Open Access How the quality of GWAS of human lifespan and health span can be improved.(Front Genet, 2013) Yashin, Anatoliy I; Arbeev, Konstantin G; Wu, Deqing; Arbeeva, Liubov S; Kulminski, Alexander M; Akushevich, Igor; Culminskaya, Irina; Stallard, Eric; Ukraintseva, Svetlana VItem Open Access Optimal Versus Realized Trajectories of Physiological Dysregulation in Aging and Their Relation to Sex-Specific Mortality Risk.(Front Public Health, 2016) Arbeev, Konstantin G; Cohen, Alan A; Arbeeva, Liubov S; Milot, Emmanuel; Stallard, Eric; Kulminski, Alexander M; Akushevich, Igor; Ukraintseva, Svetlana V; Christensen, Kaare; Yashin, Anatoliy IWhile longitudinal changes in biomarker levels and their impact on health have been characterized for individual markers, little is known about how overall marker profiles may change during aging and affect mortality risk. We implemented the recently developed measure of physiological dysregulation based on the statistical distance of biomarker profiles in the framework of the stochastic process model of aging, using data on blood pressure, heart rate, cholesterol, glucose, hematocrit, body mass index, and mortality in the Framingham original cohort. This allowed us to evaluate how physiological dysregulation is related to different aging-related characteristics such as decline in stress resistance and adaptive capacity (which typically are not observed in the data and thus can be analyzed only indirectly), and, ultimately, to estimate how such dynamic relationships increase mortality risk with age. We found that physiological dysregulation increases with age; that increased dysregulation is associated with increased mortality, and increasingly so with age; and that, in most but not all cases, there is a decreasing ability to return quickly to baseline physiological state with age. We also revealed substantial sex differences in these processes, with women becoming dysregulated more quickly but with men showing a much greater sensitivity to dysregulation in terms of mortality risk.Item Open Access Pure and Confounded Effects of Causal SNPs on Longevity: Insights for Proper Interpretation of Research Findings in GWAS of Populations with Different Genetic Structures.(Front Genet, 2016) Yashin, Anatoliy I; Zhbannikov, Ilya; Arbeeva, Liubov; Arbeev, Konstantin G; Wu, Deqing; Akushevich, Igor; Yashkin, Arseniy; Kovtun, Mikhail; Kulminski, Alexander M; Stallard, Eric; Kulminskaya, Irina; Ukraintseva, SvetlanaThis paper shows that the effects of causal SNPs on lifespan, estimated through GWAS, may be confounded and the genetic structure of the study population may be responsible for this effect. Simulation experiments show that levels of linkage disequilibrium (LD) and other parameters of the population structure describing connections between two causal SNPs may substantially influence separate estimates of the effect of the causal SNPs on lifespan. This study suggests that differences in LD levels between two causal SNP loci within two study populations may contribute to the failure to replicate previous GWAS findings. The results of this paper also show that successful replication of the results of genetic association studies does not necessarily guarantee proper interpretation of the effect of a causal SNP on lifespan.Item Open Access Puzzling role of genetic risk factors in human longevity: "risk alleles" as pro-longevity variants.(Biogerontology, 2016-02) Ukraintseva, Svetlana; Yashin, Anatoliy; Arbeev, Konstantin; Kulminski, Alexander; Akushevich, Igor; Wu, Deqing; Joshi, Gaurang; Land, Kenneth C; Stallard, EricComplex diseases are major contributors to human mortality in old age. Paradoxically, many genetic variants that have been associated with increased risks of such diseases are found in genomes of long-lived people, and do not seem to compromise longevity. Here we argue that trade-off-like and conditional effects of genes can play central role in this phenomenon and in determining longevity. Such effects may occur as result of: (i) antagonistic influence of gene on the development of different health disorders; (ii) change in the effect of gene on vulnerability to death with age (especially, from "bad" to "good"); (iii) gene-gene interaction; and (iv) gene-environment interaction, among other factors. A review of current knowledge provides many examples of genetic factors that may increase the risk of one disease but reduce chances of developing another serious health condition, or improve survival from it. Factors that may increase risk of a major disease but attenuate manifestation of physical senescence are also discussed. Overall, available evidence suggests that the influence of a genetic variant on longevity may be negative, neutral or positive, depending on a delicate balance of the detrimental and beneficial effects of such variant on multiple health and aging related traits. This balance may change with age, internal and external environments, and depend on genetic surrounding. We conclude that trade-off-like and conditional genetic effects are very common and may result in situations when a disease "risk allele" can also be a pro-longevity variant, depending on context. We emphasize importance of considering such effects in both aging research and disease prevention.Item Open Access stpm: an R package for stochastic process model.(BMC Bioinformatics, 2017-02-23) Zhbannikov, Ilya Y; Arbeev, Konstantin; Akushevich, Igor; Stallard, Eric; Yashin, Anatoliy IBACKGROUND: The Stochastic Process Model (SPM) represents a general framework for modeling the joint evolution of repeatedly measured variables and time-to-event outcomes observed in longitudinal studies, i.e., SPM relates the stochastic dynamics of variables (e.g., physiological or biological measures) with the probabilities of end points (e.g., death or system failure). SPM is applicable for analyses of longitudinal data in many research areas; however, there are no publicly available software tools that implement this methodology. RESULTS: We developed an R package stpm for the SPM-methodology. The package estimates several versions of SPM currently available in the literature including discrete- and continuous-time multidimensional models and a one-dimensional model with time-dependent parameters. Also, the package provides tools for simulation and projection of individual trajectories and hazard functions. CONCLUSION: In this paper, we present the first software implementation of the SPM-methodology by providing an R package stpm, which was verified through extensive simulation and validation studies. Future work includes further improvements of the model. Clinical and academic researchers will benefit from using the presented model and software. The R package stpm is available as open source software from the following links: https://cran.r-project.org/package=stpm (stable version) or https://github.com/izhbannikov/spm (developer version).Item Open Access The role of lipid-related genes, aging-related processes, and environment in healthspan(Aging Cell, 2013) Kulminski, Alexander M; Culminskaya, Irina; Arbeev, Konstantin G; Ukraintseva, Svetlana V; Stallard, Eric; Arbeeva, Liubov; Yashin, Anatoli IThe inherent complexity of aging-related traits can temper progress in unraveling the genetic origins of healthspan. We focus on two generations in the Framingham Heart Study, the original (FHS) and offspring (FHSO) cohorts, to determine whether aging-related processes in changing environments can substantially impact the role of lipid-related genes discovered in candidate gene (the apolipoprotein E (APOE) e2/3/4 polymorphism) and genome-wide (the APOB rs1042034 (C/T)) studies, in regulation of total cholesterol (TC) and onset of cardiovascular disease (CVD). We demonstrate that the APOE e4 allele and APOB CC genotype can play detrimental, neutral, and protective sexspecific roles in the etiology of CVD at different ages and in different environments. We document antagonistic roles for the e4 allele in the onset of CVD characterized by detrimental effects at younger ages (RR≤ 75 years = 1.49, P = 7.5×104) and protective effects at older ages (RR76+years = 0.77, P = 0.044) for FHS participants. We found that disregarding the role of aging erroneously nullifies the significant effects of the e4 allele in this sample (RR = 0.92, P = 0.387). The leading biogenetic pathways mediating genetic effects on CVD may be more relevant to lipid metabolism for APOB than APOE. Aging-related processes can modulate the strength of genetic associations with TC in the same individuals at different chronological ages. We found substantial differences in the effects of the same APOE and APOB alleles on CVD and TC across generations. The results suggest that aging-related processes in changing environments may play key roles in the genetics of healthspan. Detailed systemic integrative analyses may substantially advance the progress. © 2013 The Authors. © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.Item Open Access The Survival of Spouses Marrying Into Longevity-Enriched Families.(J Gerontol A Biol Sci Med Sci, 2017-01) Pedersen, Jacob K; Elo, Irma T; Schupf, Nicole; Perls, Thomas T; Stallard, Eric; Yashin, Anatoliy I; Christensen, KaareBACKGROUND: Studies of longevity-enriched families are an important tool to gain insight into the mechanisms of exceptionally long and healthy lives. In the Long Life Family Study, the spouses of the members of the longevity-enriched families are often used as a control group. These spouses could be expected to have better health than the background population due to shared family environment with the longevity-enriched family members and due to assortative mating. METHODS: A Danish cohort study of 5,363 offspring of long-lived siblings, born 1917-1982, and 4,498 "first spouses" of these offspring. For each offspring and spouse, 10 controls were drawn from a 5% random sample of the Danish population matched on birth year and sex. Mortality was assessed for ages 20-69 years during 1968-2013 based on prospectively collected registry data. RESULTS: During the 45-year follow-up period, 437 offspring deaths and 502 offspring spouse deaths were observed. Compared with the background population, the hazard ratio for male offspring was 0.44 (95% confidence interval [CI]: 0.38-0.50) and for female offspring it was 0.57 (95% CI: 0.49-0.66). For male spouses, the hazard ratio was 0.66 (95% CI: 0.59-0.74), whereas for female spouses it was 0.64 (95% CI: 0.54-0.76). Sensitivity analyses in restricted samples gave similar results. CONCLUSION: The mortality for ages 20-69 years of spouses marrying into longevity-enriched families is substantially lower than the mortality in the background population, although long-lived siblings participation bias may have contributed to the difference. This finding has implications for the use of spouses as controls in healthy aging and longevity studies, as environmental and/or genetic overmatching may occur.Item Open Access Trade-offs in the effects of the apolipoprotein E polymorphism on risks of diseases of the heart, cancer, and neurodegenerative disorders: insights on mechanisms from the Long Life Family Study.(Rejuvenation Res, 2015-04) Kulminski, Alexander M; Arbeev, Konstantin G; Culminskaya, Irina; Ukraintseva, Svetlana V; Stallard, Eric; Province, Michael A; Yashin, Anatoli IThe lack of evolutionary established mechanisms linking genes to age-related traits makes the problem of genetic susceptibility to health span inherently complex. One complicating factor is genetic trade-off. Here we focused on long-living participants of the Long Life Family Study (LLFS), their offspring, and spouses to: (1) Elucidate whether trade-offs in the effect of the apolipoprotein E e4 allele documented in the Framingham Heart Study (FHS) are a more general phenomenon, and (2) explore potential mechanisms generating age- and gender-specific trade-offs in the effect of the e4 allele on cancer, diseases of the heart, and neurodegenerative disorders assessed retrospectively in the LLFS populations. The e4 allele can diminish risks of cancer and diseases of the heart and confer risks of diseases of the heart in a sex-, age-, and LLFS-population-specific manner. A protective effect against cancer is seen in older long-living men and, potentially, their sons (>75 years, relative risk [RR]>75=0.48, p=0.086), which resembles our findings in the FHS. The protective effect against diseases of the heart is limited to long-living older men (RR>76=0.50, p=0.016), as well. A detrimental effect against diseases of the heart is characteristic for a normal LLFS population of male spouses and is specific for myocardial infarction (RR=3.07, p=2.1×10(-3)). These trade-offs are likely associated with two inherently different mechanisms, including disease-specific (detrimental; characteristic for a normal male population) and systemic, aging-related (protective; characteristic for older long-living men) mechanisms. The e4 allele confers risks of neurological disorders in men and women (RR=1.98, p=0.046). The results highlight the complex role of the e4 allele in genetic susceptibility to health span.