Incorporating delayed entry into the joint frailty model for recurrent events and a terminal event.

In studies of recurrent events, joint modeling approaches are often needed to allow for potential dependent censoring by a terminal event such as death. Joint frailty models for recurrent events and death with an additional dependence parameter have been studied for cases in which individuals are observed from the start of the event processes. However, samples are often selected at a later time, which results in delayed entry so that only individuals who have not yet experienced the terminal event will be included. In joint frailty models such left truncation has effects on the frailty distribution that need to be accounted for in both the recurrence process and the terminal event process, if the two are associated. We demonstrate, in a comprehensive simulation study, the effects that not adjusting for late entry can have and derive the correctly adjusted marginal likelihood, which can be expressed as a ratio of two integrals over the frailty distribution. We extend the estimation method of Liu and Huang (Stat Med 27:2665-2683, 2008. https://doi.org/10.1002/sim.3077 ) to include potential left truncation. Numerical integration is performed by Gaussian quadrature, the baseline intensities are specified as piecewise constant functions, potential covariates are assumed to have multiplicative effects on the intensities. We apply the method to estimate age-specific intensities of recurrent urinary tract infections and mortality in an older population.

Joint modeling of interval counts of recurrent events and death.

When a recurrent event process is ended by death, this may imply dependent censoring if the two processes are associated. Such dependent censoring would have to be modeled to obtain a valid inference. Moreover, the dependence between the recurrence process and the terminal event may be the primary topic of interest. Joint frailty models for recurrent events and death, which include a separate dependence parameter, have been proposed for exactly observed recurrence times. However, in many situations, only the number of events experienced during consecutive time intervals are available. We propose a method for estimating a joint frailty model based on such interval counts and observed or independently censored terminal events. The baseline rates of the two processes are modeled by piecewise constant functions, and Gaussian quadrature is used to approximate the marginal likelihood. Covariates can be included in a proportional rates setting. The observation intervals for the recurrent event counts can differ between individuals. Furthermore, we adapt a score test for the association between recurrent events and death to the setting in which only individual interval counts are observed. We study the performance of both approaches via simulation studies, and exemplify the methodology in a biodemographic study of the dependence between budding rates and mortality in the species Eleutheria dichotoma.

Information measures and design issues in the study of mortality deceleration: findings for the gamma-Gompertz model.

Mortality deceleration, or the slowing down of death rates at old ages, has been repeatedly investigated, but empirical studies of this phenomenon have produced mixed results. The scarcity of observations at the oldest ages complicates the statistical assessment of mortality deceleration, even in the parsimonious parametric framework of the gamma-Gompertz model considered here. The need for thorough verification of the ages at death can further limit the available data. As logistical constraints may only allow to validate survivors beyond a certain (high) age, samples may be restricted to a certain age range. If we can quantify the effects of the sample size and the age range on the assessment of mortality deceleration, we can make recommendations for study design. For that purpose, we propose applying the concept of the Fisher information and ideas from the theory of optimal design. We compute the Fisher information matrix in the gamma-Gompertz model, and derive information measures for comparing the performance of different study designs. We then discuss interpretations of these measures. The special case in which the frailty variance takes the value of zero and lies on the boundary of the parameter space is given particular attention. The changes in information related to varying sample sizes or age ranges are investigated for specific scenarios. The Fisher information also allows us to study the power of a likelihood ratio test to detect mortality deceleration depending on the study design. We illustrate these methods with a study of mortality among late nineteenth-century French-Canadian birth cohorts.

Trends in the Risk of Cognitive Impairment in the United States, 1996-2014.

BACKGROUND: Accumulating evidence suggests risk of cognitive impairment is declining in high-income countries. Much of this research uses longitudinal surveys in which learning over repeated tests may bias results. We analyze trends in cognitive impairment in the United States, accounting for prior test experience and selective mortality. METHODS: We use the Health and Retirement Study, a population-based, nationally representative panel dataset and include individuals ages 50 years and older in 1996-2014 (n = 32,784). We measure cognitive impairment and dementia using standard cutpoints of the modified Telephone Interview for Cognitive Status. We estimate logistic regression models for any impairment and dementia over time, adjusting for age, sex, and race/ethnicity, comparing models with and without adjustment for practice effects and education. We examine heterogeneity in trends by age, sex, race/ethnicity, and education. RESULTS: Models not controlling for test experience suggest that risk of cognitive impairment and dementia decreased over the study period. Controlling for test experience reverses the trend. In our primary models, prevalence of any cognitive impairment increased for women from 18.7% to 21.2% (annual change 0.7%, 95% confidence interval [CI], 0.1%, 1.3%) and for men from 17.6% to 21.0% (annual change 1.0%, CI, 0.5%, 1.4%). For dementia, women's annual increase was 1.7% (CI, 0.8%, 2.6%) and men's 2.0% (CI, 1.0%, 2.9%). If not for education, the increase would have been stronger. Increased risk was particularly rapid for Latinas, the least educated, and older ages. CONCLUSIONS: Risk of cognitive impairment increased from 1996 to 2014. Uncovering determinants of increasing cognitive impairment risk should become a research priority. See video abstract: http://links.lww.com/EDE/B702.

Constant mortality and fertility over age in Hydra.

Senescence, the increase in mortality and decline in fertility with age after maturity, was thought to be inevitable for all multicellular species capable of repeated breeding. Recent theoretical advances and compilations of data suggest that mortality and fertility trajectories can go up or down, or remain constant with age, but the data are scanty and problematic. Here, we present compelling evidence for constant age-specific death and reproduction rates in Hydra, a basal metazoan, in a set of experiments comprising more than 3.9 million days of observations of individual Hydra. Our data show that 2,256 Hydra from two closely related species in two laboratories in 12 cohorts, with cohort age ranging from 0 to more than 41 y, have extremely low, constant rates of mortality. Fertility rates for Hydra did not systematically decline with advancing age. This falsifies the universality of the theories of the evolution of aging that posit that all species deteriorate with age after maturity. The nonsenescent life history of Hydra implies levels of maintenance and repair that are sufficient to prevent the accumulation of damage for at least decades after maturity, far longer than the short life expectancy of Hydra in the wild. A high proportion of stem cells, constant and rapid cell turnover, few cell types, a simple body plan, and the fact that the germ line is not segregated from the soma are characteristics of Hydra that may make nonsenescence feasible. Nonsenescence may be optimal because lifetime reproduction may be enhanced more by extending adult life spans than by increasing daily fertility.

Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age.

The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

Efficient estimation of smooth distributions from coarsely grouped data.

Ungrouping binned data can be desirable for many reasons: Bins can be too coarse to allow for accurate analysis; comparisons can be hindered when different grouping approaches are used in different histograms; and the last interval is often wide and open-ended and, thus, covers a lot of information in the tail area. Age group-specific disease incidence rates and abridged life tables are examples of binned data. We propose a versatile method for ungrouping histograms that assumes that only the underlying distribution is smooth. Because of this modest assumption, the approach is suitable for most applications. The method is based on the composite link model, with a penalty added to ensure the smoothness of the target distribution. Estimates are obtained by maximizing a penalized likelihood. This maximization is performed efficiently by a version of the iteratively reweighted least-squares algorithm. Optimal values of the smoothing parameter are chosen by minimizing Akaike's Information Criterion. We demonstrate the performance of this method in a simulation study and provide several examples that illustrate the approach. Wide, open-ended intervals can be handled properly. The method can be extended to the estimation of rates when both the event counts and the exposures to risk are grouped.

Do men avoid seeking medical advice? A register-based analysis of gender-specific changes in primary healthcare use after first hospitalisation at ages 60+ in Denmark.

BACKGROUND: It remains unclear whether women's greater primary healthcare use reflects a lower treatment-seeking threshold or a health disadvantage. We address this question by studying primary healthcare use surrounding a major health shock. METHODS: This cohort study utilises routinely-collected healthcare data covering the Danish population aged 60+ years between 1996 and 2011. Using a hurdle model, we investigate levels of non-use and levels of primary healthcare use before and after first inpatient hospitalisation for stroke, myocardial infarction (MI), chronic obstructive pulmonary disease (COPD) and gastrointestinal cancers (GIC). RESULTS: Before hospitalisation, irrespective of cause, men were more likely than women to be non-users of primary healthcare (OR (95% CI): stroke 1.802 (1.731 to 1.872); MI 1.841 (1.760 to 1.922); COPD 2.160 (2.028 to 2.292); GIC 1.609 (1.525 to 1.693)). Men who were users had fewer primary healthcare contacts than women (proportional change (eß) (95% CI): stroke 0.821 (0.806 to 0.836); MI 0.796 (0.778 to 0.814); COPD 0.855 (0.832 to 0.878); GIC 0.859 (0.838 to 0.881)). Following hospitalisation, changes in the probability of being a non-user (OR (95% CI): stroke 0.965 (0.879 to 1.052); MI 0.894 (0.789 to 0.999); COPD 0.755 (0.609 to 0.900); GIC 0.895 (0.801 to 0.988)) and levels of primary healthcare use (eß (95% CI): stroke 1.113 (1.102 to 1.124); MI 1.112 (1.099 to 1.124); COPD 1.078 (1.063 to 1.093); GIC 1.097 (1.079 to 1.114)) were more pronounced among men. Gender differences widened after accounting for survival following hospitalisation. CONCLUSION: Women's consistently higher levels of primary healthcare use are likely to be explained by a combination of a lower treatment-seeking threshold and a health disadvantage resulting from better survival in bad health.

Differences in seasonal survival suggest species-specific reactions to climate change in two sympatric bat species.

Long-lived animals with a low annual reproductive output need a long time to recover from population crashes and are, thus, likely to face high extinction risk, if the current global environmental change will increase mortality rates. To aid conservation of those species, knowledge on the variability of mortality rates is essential. Unfortunately, however, individual-based multiyear data sets that are required for that have only rarely been collected for free-ranging long-lived mammals. Here, we used a five-year data set comprising activity data of 1,445 RFID-tagged individuals of two long-lived temperate zone bat species, Natterer's bats (Myotis nattereri) and Daubenton's bats (Myotis daubentonii), at their joint hibernaculum. Both species are listed as being of high conservation interest by the European Habitats Directive. Applying mixed-effects logistic regression, we explored seasonal survival differences in these two species which differ in foraging strategy and phenology. In both species, survival over the first winter of an individual's life was much lower than survival over subsequent winters. Focussing on adults only, seasonal survival patterns were largely consistent with higher winter and lower summer survival but varied in its level across years in both species. Our analyses, furthermore, highlight the importance of species-specific time periods for survival. Daubenton's bats showed a much stronger difference in survival between the two seasons than Natterer's bats. In one exceptional winter, the population of Natterer's bats crashed, while the survival of Daubenton's bats declined only moderately. While our results confirm the general seasonal survival pattern typical for hibernating mammals with higher winter than summer survival, they also show that this pattern can be reversed under particular conditions. Overall, our study points toward a high importance of specific time periods for population dynamics and suggests species-, population-, and age class-specific responses to global climate change.

Is Who you Ask Important? Concordance Between Survey and Registry Data on Medication Use Among Self- and Proxy-Respondents in the Longitudinal Study of Aging Danish Twins and the Danish 1905-Cohort Study.

BACKGROUND: This study investigates the accuracy of the reporting of medication use by proxy- and self-respondents, and it compares the prognostic value of the number of medications from survey and registry data for predicting mortality across self- and proxy-respondents. METHODS: The study is based on the linkage of the Longitudinal Study of Aging Danish Twins and the Danish 1905-Cohort Study with the Danish National Prescription Registry. We investigated the concordance between survey and registry data, and the prognostic value of medication use when assessed using survey and registry data, to predict mortality for self- and proxy-respondents at intake surveys. RESULTS: Among self-respondents, the agreement was moderate (κ = 0.52-0.58) for most therapeutic groups, whereas among proxy-respondents, the agreement was low to moderate (κ = 0.36-0.60). The magnitude of the relative differences was, generally, greater among proxies than among self-respondents. Each additional increase in the total number of medications was associated with 7%-8% mortality increase among self- and 4%-6% mortality increase among proxy-respondents in both the survey and registry data. The predictive value of the total number of medications estimated from either data source was lower among proxies (c-statistic = 0.56-0.58) than among self-respondents (c-statistic = 0.74). CONCLUSIONS: The concordance between survey and registry data regarding medication use and the predictive value of the number of medications for mortality were lower among proxy- than among self-respondents.

A novel sampling design to explore gene-longevity associations: the ECHA study.

To investigate the genetic contribution to familial similarity in longevity, we set up a novel experimental design where cousin-pairs born from siblings who were concordant or discordant for the longevity trait were analyzed. To check this design, two chromosomal regions already known to encompass longevity-related genes were examined: 6p21.3 (genes TNFalpha, TNFbeta, HSP70.1) and 11p15.5 (genes SIRT3, HRAS1, IGF2, INS, TH). Population pools of 1.6, 2.3 and 2.0 million inhabitants were screened, respectively, in Denmark, France and Italy to identify families matching the design requirements. A total of 234 trios composed by one centenarian, his/her child and a child of his/her concordant or discordant sib were collected. By using population-specific allele frequencies, we reconstructed haplotype phase and estimated the likelihood of Identical By Descent (IBD) haplotype sharing in cousin-pairs born from concordant and discordant siblings. In addition, we analyzed haplotype transmission from centenarians to offspring, and a statistically significant Transmission Ratio Distortion (TRD) was observed for both chromosomal regions in the discordant families (P=0.007 for 6p21.3 and P=0.015 for 11p15.5). In concordant families, a marginally significant TRD was observed at 6p21.3 only (P=0.06). Although no significant difference emerged between the two groups of cousin-pairs, our study gave new insights on the hindrances to recruiting a suitable sample to obtain significant IBD data on longevity-related chromosomal regions. This will allow to dimension future sampling campaigns to study-genetic basis of human longevity.

Rare catastrophic events drive population dynamics in a bat species with negligible senescence.

Bats are remarkably long-lived with lifespans exceeding even those of same-sized birds. Despite a recent interest in the extraordinary longevity of bats very little is known about the shape of mortality over age, and how mortality rates are affected by the environment. Using a large set of individual-based data collected over 19 years in four free-ranging colonies of Bechstein's bats (Myotis bechsteinii), we found no increase in the rate of mortality and no decrease in fertility demonstrating no senescence until high ages. Our finding of negligible senescence is highly unusual for long-lived mammals, grouping Bechstein's bats with long-lived seabirds. The most important determinant of adult mortality was one particular winter season, which affected all ages and sizes equally. Apart from this winter, mortality risk did not differ between the winter and the summer season. Colony membership, a proxy for local environmental conditions, also had no effect. In addition to their implications for understanding the extra-ordinary longevity in bats, our results have strong implications for the conservation of bats, since rare catastrophic mortality events can only be detected in individual based long-term field studies. With many bat species globally threatened, such data are crucial for the successful implementation of conservation programs.

Handgrip strength among nonagenarians and centenarians in three European regions.

BACKGROUND: Handgrip strength is an important predictor of disability and mortality among old people. The aim was to compare the grip strength among very old people in three regions of Europe. METHODS: In this substudy of the European Challenge for Healthy Aging project, only the long-lived probands were included. The maximum value of three measurements of handgrip strength was selected for the analysis. Adjustment for factors known to be correlated with grip strength was made by linear regression. RESULTS: Among 598 very old people (median age = 98 years) a clear North-South gradient was observed: For men, handgrip strength dropped from 24.2 kg in Southern Denmark to 20.8 kg in Languedoc-Roussillon, France and 14.2 kg in Calabria, Italy (p < .0001), whereas for women the drop was smaller (from 12.2 to 9.2 kg; p = .0021). The difference remains significant after adjustment for age, gender, housing, knee height, Activities of Daily Living (ADL) scale score, score on the Six-Item Mini-Mental State Examination, chair stand, and number of age-related diseases, although these factors explain two thirds of the variation in handgrip strength. CONCLUSIONS: Among nonagenarians and centenarians in three different European regions, we found a significant North-South gradient in handgrip strength with substantially lower values in Calabria. This finding may be due both to population background differences (e.g., genetic variations, birth weight, childhood growth) and to sociocultural differences (e.g., lifestyle, health care).

Age-specific demography in Plantago: uncovering age-dependent mortality in a natural population.

Accurate measures of age-dependent mortality are critical to life-history analysis and measures of fitness, yet these measures are difficult to obtain in natural populations. Age-dependent mortality patterns can be obscured not only by seasonal variation in environmental conditions and reproduction but also by changes in the heterogeneity among individuals in the population over time due to selection. This study of Plantago lanceolata uses longitudinal data from a field study with a large number of individuals to develop a model to estimate the shape of the baseline hazard function that represents the age-dependent risk of mortality. The model developed here uses both constant (genetics, spatial location) and time-varying (temperature, rainfall, reproduction, size) covariates not only to estimate the underlying mortality pattern but also to demonstrate that the risk of mortality associated with fitness components can change with time/age. Moreover, this analysis suggests that increasing size after reproductive maturity may allow this plant species to escape from demographic senescence.

Young and intense: FoxP2 immunoreactivity in Area X varies with age, song stereotypy, and singing in male zebra finches.

FOXP2 is a transcription factor functionally relevant for learned vocalizations in humans and songbirds. In songbirds, FoxP2 mRNA expression in the medium spiny neurons of the basal ganglia song nucleus Area X is developmentally regulated and varies with singing conditions in different social contexts. How individual neurons in Area X change FoxP2 expression across development and in social contexts is not known, however. Here we address this critical gap in our understanding of FoxP2 as a link between neuronal networks and behavior. We used a statistically unbiased analysis of FoxP2-immunoreactivity (FoxP2-IR) on a neuron-by-neuron basis and found a bimodal distribution of FoxP2-IR neurons in Area X: weakly-stained and intensely-stained. The density of intensely-stained FoxP2-IR neurons was 10 times higher in juveniles than in adults, exponentially decreased with age, and was negatively correlated with adult song stability. Three-week old neurons labeled with BrdU were more than five times as likely to be intensely-stained than weakly-stained. The density of FoxP2-IR putative migratory neurons with fusiform-shaped nuclei substantially decreased as birds aged. The density of intensely-stained FoxP2-IR neurons was not affected by singing whereas the density of weakly-stained FoxP2-IR neurons was. Together, these data indicate that young Area X medium spiny neurons express FoxP2 at high levels and decrease expression as they become integrated into existing neural circuits. Once integrated, levels of FoxP2 expression correlate with singing behavior. Together, these findings raise the possibility that FoxP2 levels may orchestrate song learning and song stereotypy in adults by a common mechanism.

Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study.

Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10(-5) , respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.

Handgrip strength: indications of paternal inheritance in three European regions.

BACKGROUND: Handgrip strength is an indicator of overall muscle strength. Poor handgrip strength is a risk factor for disability and mortality. We aimed to investigate the pattern of inheritance of handgrip strength in a sample of parent-offspring pairs from three different European regions in Denmark, France, and Italy. METHODS: In this substudy of the European Challenge for Healthy Aging study, handgrip strength was measured in 290 subjects aged 90 years and older and in one of their offspring. RESULTS: When all pairs were considered together, parental and offspring handgrip strength were weakly correlated (r = .16; p < .01). However, paternal-offspring correlation was significantly higher than maternal-offspring correlation (r = .26; confidence interval [CI]: 0.11-0.41 versus r = .03; CI: -0.14 to 0.19; p = .04). This difference was particularly marked for daughters (r = -.07; CI: -0.29 to 0.16 for mother-daughter correlation versus r = .31; CI: 0.11-0.49 for father-daughter; p = .01) compared with sons (r = .12; CI: -0.13 to 0.36 for mother-son correlation versus r = .25; CI: 0.00-0.46 for father-son; p = .47). Father-daughter correlation remained higher than mother-daughter when analyses were performed with 144 nondependent parents (r = .32; CI: 0.04; 0.55 versus r = -.25; CI: -0.61 to 0.21; p = .03). These results were similarly observed in the three regions of the study, where mean levels of handgrip strength strongly differed. CONCLUSIONS: It suggests that age-related effects on functional health among women could be mediated more through the paternal line than the maternal.

Modulation models for seasonal time series and incidence tables.

We model monthly disease counts on an age-time grid using the two-dimensional varying-coefficient Poisson regression. Since the marginal profile of counts shows a very strong and varying annual cycle, sine and cosine regressors model periodicity, but their coefficients are allowed to vary smoothly over the age and time plane. The coefficient surfaces are estimated using a relatively large tensor product B-spline basis. Smoothness is tuned using difference penalties on the rows and columns of the tensor product coefficients. Heavy over-dispersion occurs, making it impossible to use Akaike's information criterion or Bayesian information criterion based on a Poisson likelihood. It is handled by selective weighting of part of the data and by the use of extended quasi-likelihood. Very efficient computation is achieved with fast array algorithms. The model is applied to monthly deaths due to respiratory diseases, for U.S. females during 1959-1998 and for ages 51-100.

Symmetrically dividing cells of the fission yeast schizosaccharomyces pombe do age.

Theories of the evolution of senescence state that symmetrically dividing organisms do not senesce. However, this view is challenged by experimental evidence. We measured by immunofluorescence the occurrence and intensity of protein carbonylation in single and symmetrically dividing cells of Schizosaccharomyces pombe. Cells of S. pombe show different levels of carbonylated proteins. Most cells have little damage, a few show a lot, an observation consistent with the gradual accumulation of carbonylation over time. At reproduction, oxidized proteins are shared between the two resulting cells. These results indicate that S. pombe does age, but does so in a different way from other studied species. Damaged cells give rise to damaged cells. The fact that cells with no or few carbonylated proteins constitute the main part of the population can explain why, although age is not reset to zero in one of the cells during division, the pool of young cells remains large enough to prevent the rapid extinction of the population.