Rune Lindahl-Jacobsen

The Male-Female Health-Survival Paradox and Sex Differences in Cohort Life Expectancy in Utah, Denmark and Sweden 1850-1910

PURPOSE In Utah, the prevalence of unhealthy male risk behaviors are lower than in most other male populations, whereas women experience higher mortality risk because of higher fertility rates. Therefore, we hypothesize that the Utah sex differential in mortality would be small and less than in Sweden and Denmark. METHODS Life tables from Utah, Denmark, and Sweden were used to calculate cohort life expectancies for men and women born in 1850-1910. RESULTS The sex difference in cohort life expectancy was similar or larger in Utah when compared with Denmark and Sweden. The change over time in the sex differences in cohort life expectancy was approximately 2 years smaller for active Mormons in Utah than for other groups suggesting lifestyle as an important component for the overall change seen in cohort life expectancy. Sex differences in cohort life expectancy at the age of 50 years were similar for individuals actively affiliated with the Church of Jesus Christ of Latter-day Saints and for Denmark and Sweden. CONCLUSIONS The hypothesis that a smaller sex difference in cohort life expectancies in Utah would be detected in relation to Denmark and Sweden was not supported. In Utah, the male-female differences in life expectancy remain substantial pointing toward biological mechanisms or other unmeasured risk factors.

CLU Genetic Variants and Cognitive Decline among Elderly and Oldest Old

The CLU gene is one of the prime genetic candidates associated with Alzheimers disease. In the present study CLU genotypes and haplotypes were associated with baseline cognition and the rate of cognitive decline in two cohorts, the Danish 1905 birth cohort (93 years of age in 1998) and the Longitudinal Study of Aging Danish twins (LSADT) (73–83 year old twins in 1997). Both Mini Mental State Examination (MMSE) and a cognitive composite score was attained up to six times for up to 10 years and analysed using random effects models and vital status. The rs11136000 T allele was associated with better baseline cognitive performance both in the LSADT (effect on intercept: 0.41 95% CI [−0.04; 0.87]) and the 1905 birth cohort (effect on intercept: 0.28 95% CI [0.01; 0.55]), although it did not reach significance in the LSADT cohort. However, the rs11136000 T allele was significantly associated with a steeper decline (effect on slope: −0.06 95% CI [−0.11; −0.01]) in the LSADT cohort, but not in the 1905 birth cohort. Haplotype analyses revealed that carriers of the common rs11136000, rs1532278 and rs9331888 TTC haplotype (36%) in the CLU gene performed cognitively better than non-carriers in the 1905 birth cohort (effect on intercept: 0.50 95% CI [0.12; 0.91]) and carriers of a rare TCC haplotype (1%) performed worse on the cognitive composite score (effect on intercept: −1.51 95% CI [−2.92; −0.06]). The association between the TTC haplotype and better cognitive composite score was higher among those surviving past the age of 98 (p = 0.014), and among these the TTC haplotype was borderline associated with a steep decline (effect on slope: −0.13 95% CI [−0.27; 0.00]). In summery CLU genetic variants associate with cognition in two cohorts, but the genetic effect of CLU seems to regress toward the mean when aging.

Birth cohort differences in the prevalence of longevity-associated variants in APOE and FOXO3A in Danish long-lived individuals

Gene variants found to associate with human longevity in one population rarely replicate in other populations. The lack of consistent findings may partly be explained by genetic heterogeneity among long-lived individuals due to cohort differences in survival probability. In most high-income countries the probability of reaching e.g. 100years increases by 50-100% per decade, i.e. there is far less selection in more recent cohorts. Here we investigate the cohort specificity of variants in the APOE and FOXO3A genes by comparing the frequencies of the APOE ε4 allele and the minor alleles of two variants in FOXO3A at age 95+ and 100+ in 2712 individuals from the genetically homogeneous Danish birth cohorts 1895-96, 1905, 1910-11, and 1915. Generally, we find a decrease in the allele frequencies of the investigated APOE and FOXO3A variants in individuals from more recent birth cohorts. Assuming a recessive model, this negative trend is significant in 95+ year old individuals homozygous for the APOE ε4 allele (P=0.026) or for the FOXO3A rs7762395 minor allele (P=0.048). For the APOE ε4 allele, the significance is further strengthened when restricting to women (P=0.006). Supportive, but non-significant, trends are found for two of the three tested variants in individuals older than 100years. Altogether, this indicates that cohort differences in selection pressure on survival to the highest ages are reflected in the prevalence of longevity gene variants. Although the effect seems to be moderate, our findings could have an impact on genetic studies of human longevity.

Effects of the APOE ε2 Allele on Mortality and Cognitive Function in the Oldest Old

Some studies indicate that the APOE ε2 allele may have a protective effect on mortality and mental health among the elderly adults. We investigated the effect of the APOE ε2 allele on cognitive function and mortality in 1651 members of the virtually extinct Danish 1905 birth cohort. We found no protective effect of the APOE ε2 allele on mortality compared with the APOE ε3 allele. The point estimates indicated an increased protection against cognitive decline over time for persons with the APOE ε2 allele. Cognitive score did not significantly modify the mortality risk of the various APOE genotypes. We did not find a protective effect of the APOE ε2 allele on mortality among the oldest old, but in agreement with our previous findings, we found a 22% increased mortality risk for APOE ε4 carriers. The APOE ε2 allele may be protective on cognitive decline among the oldest old.

Remaining Life Expectancy With and Without Polypharmacy: A Register-Based Study of Swedes Aged 65 Years and Older

Objectives To investigate the remaining life expectancy with and without polypharmacy for Swedish women and men aged 65 years and older. Design Age-specific prevalence of polypharmacy from the nationwide Swedish Prescribed Drug Register (SPDR) combined with life tables from Statistics Sweden was used to calculate the survival function and remaining life expectancy with and without polypharmacy according to the Sullivan method. Setting Nationwide register-based study. Participants A total of 1,347,564 individuals aged 65 years and older who had been prescribed and dispensed a drug from July 1 to September 30, 2008. Measurements Polypharmacy was defined as the concurrent use of 5 or more drugs. Results At age 65 years, approximately 8 years of the 20 remaining years of life (41%) can be expected to be lived with polypharmacy. More than half of the remaining life expectancy will be spent with polypharmacy after the age of 75 years. Women had a longer life expectancy, but also lived more years with polypharmacy than men. Discussion Older women and men spend a considerable proportion of their lives with polypharmacy. Conclusion Given the negative health outcomes associated with polypharmacy, efforts should be made to reduce the number of years older adults spend with polypharmacy to minimize the risk of unwanted consequences.

Rise, stagnation, and rise of Danish women's life expectancy

Significance Life expectancy is the most commonly used measure of health status in a population. Life expectancy has increased rapidly in most western populations over the past two centuries. There has been an ongoing debate about the relative contribution of cohort and period effects on a nation’s life expectancy, but few concrete examples of strong cohort effects exist. In this study, we use demographic approaches to study cohort effects on the life expectancy of Danish women. We identify a clear-cut and strong cohort effect: the case of the interwar generations of Danish women. Health conditions change from year to year, with a general tendency in many countries for improvement. These conditions also change from one birth cohort to another: some generations suffer more adverse events in childhood, smoke more heavily, eat poorer diets, etc., than generations born earlier or later. Because it is difficult to disentangle period effects from cohort effects, demographers, epidemiologists, actuaries, and other population scientists often disagree about cohort effects’ relative importance. In particular, some advocate forecasts of life expectancy based on period trends; others favor forecasts that hinge on cohort differences. We use a combination of age decomposition and exchange of survival probabilities between countries to study the remarkable recent history of female life expectancy in Denmark, a saga of rising, stagnating, and now again rising lifespans. The gap between female life expectancy in Denmark vs. Sweden grew to 3.5 y in the period 1975–2000. When we assumed that Danish women born 1915–1945 had the same survival probabilities as Swedish women, the gap remained small and roughly constant. Hence, the lower Danish life expectancy is caused by these cohorts and is not attributable to period effects.

Risk of Sex-Specific Cancers in Opposite-Sex and Same-Sex Twins in Denmark and Sweden

Background: Increasing evidence shows that some cancers originate in utero. It is hypothesized that elevated exposure to some steroid hormones might increase cancer risk and that hormone transfer between twin fetuses could result in different prenatal exposure to testosterone. Methods: This large-scale prospective twin study compared opposite-sex (OS) and same-sex (SS) twins to test the impact of intrauterine exposures on cancer risk. On the basis of the Danish and Swedish twin and cancer registries, we calculated incidence rate ratios for OS and SS twins, whereas standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated for OS/SS twins compared with the general population. Results: A total of 18,001 cancers were identified during 1943–2009. No significant differences were observed between OS and SS twins, neither for the sex-specific cancers nor for cancer at all sites. All-cause cancer was slightly reduced for OS and SS twins compared with the general population, significant for OS males (SIR, 0.95; 95% CI, 0.92–0.98) and for SS males and females (SIR, 0.97; 95% CI, 0.94–0.99). Conclusions: Our data suggest that having a male co-twin—which may entail higher exposure to prenatal testosterone—does not increase the risk of sex-specific cancers in OS females. Furthermore, the study supports that twinning per se is not a risk factor of cancer. Impact: Findings are reassuring, as they fail to provide evidence for the hypothesis that endocrine or other difference in the in utero milieu affects the risk of sex-specific cancers. Cancer Epidemiol Biomarkers Prev; 24(10); 1622–8. ©2015 AACR.

Women live longer than men even during severe famines and epidemics

Significance Women live longer than men in nearly all populations today. Some research focuses on the biological origins of the female advantage; other research stresses the significance of social factors. We studied male–female survival differences in populations of slaves and populations exposed to severe famines and epidemics. We find that even when mortality was very high, women lived longer on average than men. Most of the female advantage was due to differences in mortality among infants: baby girls were able to survive harsh conditions better than baby boys. These results support the view that the female survival advantage is modulated by a complex interaction of biological environmental and social factors. Women in almost all modern populations live longer than men. Research to date provides evidence for both biological and social factors influencing this gender gap. Conditions when both men and women experience extremely high levels of mortality risk are unexplored sources of information. We investigate the survival of both sexes in seven populations under extreme conditions from famines, epidemics, and slavery. Women survived better than men: In all populations, they had lower mortality across almost all ages, and, with the exception of one slave population, they lived longer on average than men. Gender differences in infant mortality contributed the most to the gender gap in life expectancy, indicating that newborn girls were able to survive extreme mortality hazards better than newborn boys. Our results confirm the ubiquity of a female survival advantage even when mortality is extraordinarily high. The hypothesis that the survival advantage of women has fundamental biological underpinnings is supported by the fact that under very harsh conditions females survive better than males even at infant ages when behavioral and social differences may be minimal or favor males. Our findings also indicate that the female advantage differs across environments and is modulated by social factors.

Parental age at delivery and a man's semen quality

STUDY QUESTION Is parental age at delivery associated with a mans semen quality? SUMMARY ANSWER In this large register-based study both mothers and fathers age are found to have minimal effects on semen quality in men. WHAT IS KNOWN ALREADY Both maternal and paternal age have been associated with a range of adverse health effects in the offspring. Given the varied health effects of parental age upon offspring, and the sensitivity of genital development to external factors, it is plausible that the age of a mans mother and father at conception may impact his reproductive health. To our knowledge this is the first examination of the effects of parental age on semen quality. STUDY DESIGN, SIZE, DURATION A retrospective cohort study of 10 965 men with semen data and parental data. PARTICIPANTS/MATERIALS, SETTING, METHODS The study was based on Danish men referred to the Copenhagen Sperm Analysis Laboratory due to infertility in their partnership. Men born from 1960 and delivering a semen sample until year 2000 were included. The men were linked to the Danish Civil Registration System to obtain information on parents age at delivery. Logistic regression analyses were used to calculate odds ratios and 95% confidence intervals for impaired semen quality. Linear regression analyses were used to examine a relationship between semen parameters and paternal age. MAIN RESULTS AND THE ROLE OF CHANCE There were no convincing effect of either mothers or fathers age on a mans semen quality. As no trends were noted, the few statistically significant results are likely attributable to chance. LIMITATIONS, REASONS FOR CAUTION Information regarding individual subject characteristics which may impact sperm production (i.e. smoking, BMI) were not available. While our sample size was large, we cannot exclude the possibility that a trend may have been identified with a still larger sample. In addition, the Danish Civil Registration System is merely administrative and hence does not discriminate between biological and adopted children. However, the low rate of adoption (≈2%) suggests that misclassification would have a minimal impact. The men were all referred to the laboratory for infertility problems in their partnership and, therefore, do not represent the general population. We, however, compared semen quality among men within the cohort, and it is therefore less important whether they, in fact, represent the general population. WIDER IMPLICATIONS OF THE FINDINGS The current study found no link between parental age and a sons semen quality, suggesting other factors may explain recent impairments in mens reproductive health. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Hans and Nora Buchards Fund and the Kirsten and Freddy Johansens Fund. No competing interests. TRIAL REGISTRATION NUMBER Not relevant.

Comparison of non-parametric methods for ungrouping coarsely aggregated data

BackgroundHistograms are a common tool to estimate densities non-parametrically. They are extensively encountered in health sciences to summarize data in a compact format. Examples are age-specific distributions of death or onset of diseases grouped in 5-years age classes with an open-ended age group at the highest ages. When histogram intervals are too coarse, information is lost and comparison between histograms with different boundaries is arduous. In these cases it is useful to estimate detailed distributions from grouped data.MethodsFrom an extensive literature search we identify five methods for ungrouping count data. We compare the performance of two spline interpolation methods, two kernel density estimators and a penalized composite link model first via a simulation study and then with empirical data obtained from the NORDCAN Database. All methods analyzed can be used to estimate differently shaped distributions; can handle unequal interval length; and allow stretches of 0 counts.ResultsThe methods show similar performance when the grouping scheme is relatively narrow, i.e. 5-years age classes. With coarser age intervals, i.e. in the presence of open-ended age groups, the penalized composite link model performs the best.ConclusionWe give an overview and test different methods to estimate detailed distributions from grouped count data. Health researchers can benefit from these versatile methods, which are ready for use in the statistical software R. We recommend using the penalized composite link model when data are grouped in wide age classes.