Screening for carcinoma in situ in the contralateral testicle in patients with testicular cancer: a population-based study.

BACKGROUND: Screening programmes for contralateral carcinoma in situ (CIS) testis in patients with unilateral germ-cell cancer (GCC) have never been evaluated. We investigated the effect of screening for contralateral CIS in a large nation-wide, population-based study. PATIENTS AND METHODS: A contralateral single-site biopsy was offered to 4130 patients in whom GCC had been diagnosed in 1984-2007 (screened cohort); 462 patients in whom GCC was diagnosed in 1984-1988 comprised the unscreened cohort. Cases with CIS were offered radiotherapy. Initially CIS-negative biopsies in patients with metachronous GCC were revised according to today's standards. Risk for metachronous GCC was estimated using cumulative incidence and the Cox proportional hazards model. RESULTS: In the screened cohort, contralateral CIS was found in 181 (4.4%) patients. The cumulative incidence of metachronous GCC after 20 years was 1.9% in the screened cohort and 3.1% in the unscreened cohort (P = 0.097), hazard ratio (HR) for the unscreened cohort: 1.59 (P = 0.144). Expert revision with contemporary methodology of CIS-negative biopsy samples from patients with metachronous cancer revealed CIS in 17 out of 45 (38%) cases. Decreased risks for metachronous GCC were related to older age at diagnosis (HR 0.52 per 10 years, P < 0.001) and chemotherapy (HR 0.35, P = 0.002). Limitations include the small number of patients in the unscreened cohort and the retrospective study design. CONCLUSIONS: Our evaluation of a national population-based screening programme for contralateral CIS in patients with testicular cancer showed no significant difference in the risk for metachronous GCC between a screened and an unscreened cohort. Single-site biopsy including modern immunohistochemistry does not identify all cases of CIS.

Abdominal wall defects in Denmark, 1970-89.

In the last two to three decades, increasing rates of gastroschisis but not of omphalocele have been reported from different parts of the world. The present study represents a register containing 469 children born with abdominal wall defects based on data retrieved from 20 birth cohorts (1970-89) in three nationwide registries. A tentative estimate of the completeness as regards identification of liveborn and stillborn infants is a minimum of 95% and 90% respectively. All cases were reclassified to 166 cases of gastroschisis, 258 of omphalocele and 16 of gross abdominal wall defect. The average point prevalence at birth of gastroschisis was 1.33 per 10 000 live and stillbirths. During the first decade, an increase in prevalence occurred culminating in 1976, followed by a decrease reaching its initial value in 1983 and then a new increase. Overall, no significant linear trend could be demonstrated for the entire period. The average point prevalence at birth for omphalocele was 2.07 and for gross abdominal wall defect 0.12 per 10 000 live and stillbirths with no significant change in the period. The geographical distribution of gastroschisis and omphalocele showed no difference per county.

The heritability of mortality due to heart diseases: a correlated frailty model applied to Danish twins.

Data of the Danish Twin Registry on monozygotic and dizygotic twins are used to analyse genetic and environmental influences on susceptibility to heart diseases for males and females, respectively. The sample includes 7955 like-sexed twin pairs born between 1870 and 1930. Follow-up was from 1 January 1943 to 31 December 1993 which results in truncation (twin pairs were included in the study if both individuals were still alive at the beginning of the follow-up) and censoring (nearly 40% of the study population was still alive at the end of the follow-up). We use the correlated gamma-frailty model for the genetic analysis of frailty to account for this censoring and truncation. During the follow-up 9370 deaths occurred, 3393 deaths were due to heart diseases in general, including 2476 deaths due to coronary heart disease (CHD). Proportions of variance of frailty attributable to genetic and environmental factors were analyzed using the structural equation model approach. Different standard biometric models are fitted to the data to evaluate the magnitude and nature of genetic and environmental factors on mortality. Using the best fitting model heritability of frailty (liability to death) was found to be 0.55 (0.07) and 0.53 (0.11) with respect to heart diseases and CHD, respectively, for males and 0.52 (0.10) and 0.58 (0.14) for females in a parametric analysis. A semi-parametric analysis shows very similar results. These analyses may indicate the existence of a strong genetic influence on individual frailty associated with mortality caused by heart diseases and CHD in both, males and females. The nature of genetic influences on frailty with respect to heart diseases and CHD is probably additive. No evidence for dominance and shared environment was found.

Cardiovascular mortality in twins and the fetal origins hypothesis.

The intrauterine growth patterns for twins are characterized by normal development during the first two trimesters and reduced growth during the third trimester. According to the fetal origins hypothesis this growth pattern is associated with risk factors for cardiovascular morbidity and mortality. We studied cause-specific mortality of 19,986 Danish twin individuals from the birth cohorts 1870-1930 followed from 1952 through 1993. Despite the large sample size and follow-up period we were not able to detect any difference between twins and the general population with regard to all-cause mortality or cardiovascular mortality. Hence, the intrauterine growth retardation experienced by twins does not result in any "fetal programming" of cardiovascular diseases. There is still an important role for twins (and other sibs) to play in the testing of the fetal origins hypothesis, namely in studies of intra-pair differences, which can assess the role of genetic confounding in the association between fetal growth and later health outcome.

Breast cancer risk in male twins: joint analyses of four twin cohorts in Denmark, Finland, Sweden and the United States.

To test the hypothesis that in utero exposure to high levels of oestrogen increases the risk of male breast cancer, we followed 115 235 male twins for more than 3.5 million person-years at risk. We observed 11 cases of male breast cancer versus 16.16 expected based on national rates (standardized rate ratio 0.68, 95% confidence interval 0.34-1.22) and conclude that any adverse influence of in utero oestrogen exposure is likely to be small.

Genetic and environmental influences on functional abilities in Danish twins aged 75 years and older.

BACKGROUND: Functional abilities vary widely among elderly persons. The determinants of this variation are probably multiple and include normal aging processes as well as disease expression. This study estimates the relative importance of genetic and environmental factors to variation in functional abilities in elderly persons. METHODS: We conducted a survey among all Danish twins aged 75 years and older who were identified in the population-based Danish Twin Registry. Interviews were conducted with 77% (7% by proxy responders) of the 3099 individuals in the study population. Functional abilities were assessed by validated Danish survey instruments and were scored on three scales. Heritability (proportion of the population variance attributable to genetic variation) was estimated using structural equation analyses. RESULTS: Structural equation analyses revealed a substantial heritability (34%-47%) for the three functional ability scores among the women aged 80 years and older compared with a more modest heritability (15%-34%) among the women aged 75-79 years. The remaining variation could be attributed to individuals' nonfamilial environments. Comparisons of the functional abilities of twins with living versus deceased co-twins also suggested a difference in the genetic influence for the two age groups. Although heritability estimates were uniformly low in the male participant sample, the size of the sample was not sufficiently large to allow for precise estimates of heritability. CONCLUSION: For women we found that the effect of genetic factors on functional abilities increases with age and accounts for one third to one half of the variation among individuals aged 80 years and older. An understanding of the genetic mechanisms underlying functional abilities in the oldest individuals may enhance the possibilities for improving health in the elderly population by modifying environmental factors.

Handedness and mortality: a follow-up study of Danish twins born between 1900 and 1910.

The declining prevalence of left-handed individuals with increasing age has led to two main avenues of hypotheses; the association is due either (1) to a birth cohort effect and/or an age effect caused by a switch to right-handedness with advancing age or (2) to mortality selection that reduces survival in left-handed individuals, or both. It is uncertain whether a cohort or age effect can explain the decline in age-related prevalence, and conflicting evidence exists in favor of the mortality hypothesis. We compared mortality in a subgroup of 118 opposite-handed twin pairs by counting in how many instances the right-handed twin died first. There was no evidence of differential survival between right-handed and non-right-handed individuals in the entire 1900-1910 cohort. With respect to the number of right-handed twins who died first, there was no material disadvantage among those who were not right-handed. In 60% (95% confidence interval = 49.0-71.5%) of dizygotic pairs, the right-handed twins died first. In 50% of monozygotic pairs, right-handed twins died first. The prevalence of not being right-handed was higher among males (9.2%) than females (6.5%); there was a similar frequency of non-right-handedness in monozygotic (8.0%) and dizygotic (7.8%) twins. We did not find evidence of excess mortality among non-right-handed adult twins in this follow-up study.

Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland.

BACKGROUND: The contribution of hereditary factors to the causation of sporadic cancer is unclear. Studies of twins make it possible to estimate the overall contribution of inherited genes to the development of malignant diseases. METHODS: We combined data on 44,788 pairs of twins listed in the Swedish, Danish, and Finnish twin registries in order to assess the risks of cancer at 28 anatomical sites for the twins of persons with cancer. Statistical modeling was used to estimate the relative importance of heritable and environmental factors in causing cancer at 11 of those sites. RESULTS: At least one cancer occurred in 10,803 persons among 9512 pairs of twins. An increased risk was found among the twins of affected persons for stomach, colorectal, lung, breast, and prostate cancer. Statistically significant effects of heritable factors were observed for prostate cancer (42 percent; 95 percent confidence interval, 29 to 50 percent), colorectal cancer (35 percent; 95 percent confidence interval, 10 to 48 percent), and breast cancer (27 percent; 95 percent confidence interval, 4 to 41 percent). CONCLUSIONS: Inherited genetic factors make a minor contribution to susceptibility to most types of neoplasms. This finding indicates that the environment has the principal role in causing sporadic cancer. The relatively large effect of heritability in cancer at a few sites suggests major gaps in our knowledge of the genetics of cancer.

A Danish population-based twin study on general health in the elderly.

OBJECTIVES: To study the relative influence of genetic and environmental factors on self-rated health and hospitalization patterns in the elderly. METHODS: A survey among all 3,099 Danish twins ages 75 years and older identified in the Danish Twin Registry. An interview was conducted with 77% of the twins. The number of hospitalizations in the previous 18 years was obtained through register linkage, thereby obtaining health information on 96% of the study population, including all nonresponders. RESULTS: Structural equation modeling suggested that approximately a quarter of the variation in the liability to self-reported health and the number of hospitalizations could be attributed to genetic factors. The remaining variation was most likely due to nonfamilial environment. Analyses of the hospitalization patterns of proxy responders and nonresponders suggest that the estimates of the genetic influence on health outcomes in the study are conservative. DISCUSSION: The present study indicates that variation in general health among the elderly is partly explained by genetic factors.

The genetic component of discrete disability traits: an analysis using liability models with age-dependent thresholds.

The presence of familial and genetic effects in the Activities-of-Daily-Life (ADL) data collected in the first wave of the 1995 Longitudinal Study of Aging of Danish Twins (LSADT) older than 75 is tested using multithreshold liability models of disability with age-dependent thresholds. These models are developed for discrete scores represented by five disability scales of male and female Danish twins. The presence of familial effects is revealed in all five scales of disability data for females and in three scales of data for males. Genetic effects are found to be significant in all four levels of aggregation of the Upper Limb-T (T = tiredness) disability scale for females and in the PADL-H (H = need for help) scale for males. Genetic effects are also pronounced in the Mobility-T scale for females and in the Lower Limb-T scale for males and females. For females, the genetic effects in the T-scale seem to be more pronounced than in the H-scale. For males, genetic effects are more pronounced in the H-scale. The estimates for MZ correlations in liability tend to be higher than the estimates for DZ correlations in almost all cases, which suggests that additional genetic effects may be revealed should the sample size of the ADL data be increased.

A population-based study of Graves' disease in Danish twins.

OBJECTIVE: The aetiology of Graves' disease (GD) is generally thought to fit a multi-factorial pattern of inheritance in which clinical disease develops on the basis of genetic susceptibility interacting with environmental and endogenous factors. In previous twin studies the probandwise concordance rates for hyperthyroidism were as high as 0.86 in monozygotic twins and 0.20 in dizygotic twins, indicating a very strong genetic influence. In these studies, however, no effort was made to distinguish between GD and non-autoimmune hyperthyroidism, and one study also included patients with simple non-toxic goitre, hampering if not invalidating any conclusions. The aim of the present study was to determine whether there is a genetic contribution in the aetiology of GD. DESIGN: Historical cohort study of pairs of same-sex twins, with information on GD being gathered by questionnaire surveys in the 1950s and 1960s. All available hospital material was sought to verify the diagnosis, which was assigned on the basis of clinical and histopathological evidence. The healthy co-twins were followed through middle age by questionnaire surveys in the 1970s and 1980s. PATIENTS: Same-sex twin individuals born between 1870-1920, included in a population-based nationwide register. A total of 118 subjects indicated hospitalization due to GD. A hospital record was available in 76 subjects. Of these, 55 (46 females and 9 males) could be classified as having GD. MEASUREMENTS: Pairwise and probandwise concordance rates for GD in monozygotic and dizygotic twin pairs. RESULTS: The probandwise concordance rates were 0.36 for monozygotic pairs and 0 for dizygotic pairs. The pairwise concordance rates were 0.22 and 0 for monozygotic and dizygotic pairs, respectively. The concordance rates were significantly (P = 0.012) higher in monozygotic than in dizygotic pairs. CONCLUSIONS: These results confirm that genetic factors play an important role in the aetiology of Graves' disease. However, they may not be as powerful as previously thought.

Biodemographic trajectories of longevity.

Old-age survival has increased substantially since 1950. Death rates decelerate with age for insects, worms, and yeast, as well as humans. This evidence of extended postreproductive survival is puzzling. Three biodemographic insights--concerning the correlation of death rates across age, individual differences in survival chances, and induced alterations in age patterns of fertility and mortality--offer clues and suggest research on the failure of complicated systems, on new demographic equations for evolutionary theory, and on fertility-longevity interactions. Nongenetic changes account for increases in human life-spans to date. Explication of these causes and the genetic license for extended survival, as well as discovery of genes and other survival attributes affecting longevity, will lead to even longer lives.

[Clinics for counseling on cancer genetics. Experiences with genetic studies and counseling on familial breast cancer and colorectal cancer]. / Cancergenetisk rådgivningsklinik. Erfaringer med genetisk udredning og rådgivning ved familiaer cancer mammae og familiaer cancer colorectalis.

Five to ten percent of cases of breast cancer and colorectal cancer are familial. These families can be divided into high-risk families and moderate-risk families. Cancer in high-risk families can often be explained by dominant inheritance of a gene causing increased susceptibility to cancer. There is a great demand for genetic counseling in these families, and the structure of and experiences from a familial cancer clinic at Odense University Hospital is described. The establishment of a familial cancer clinic involves three steps: 1) Identification of families with increased cancer susceptibility; 2) Molecular tests to identify gene carriers; 3) Clinical examinations for early detection of tumors. Achievement of these three steps requires the involvement of several medical specialties to ensure patient care. Experience with familial cancer clinics is still limited and the involvement of genetic testing and clinical examination programs at risk individuals are insufficiently examined. The rapidly improving techniques for genetic testing make it urgent that it is implemented as part of already established clinical programs.

How heritable is individual susceptibility to death? The results of an analysis of survival data on Danish, Swedish and Finnish twins.

Molecular epidemiological studies confirm a substantial contribution of individual genes to variability in susceptibility to disease and death for humans. To evaluate the contribution of all genes to susceptibility and to estimate individual survival characteristics, survival data on related individuals (eg twins or other relatives) are needed. Correlated gamma-frailty models of bivariate survival are used in a joint analysis of survival data on more than 31,000 pairs of Danish, Swedish and Finnish male and female twins using the maximum likelihood method. Additive decomposition of frailty into genetic and environmental components is used to estimate heritability in frailty. The estimate of the standard deviation of frailty from the pooled data is about 1.5. The hypothesis that variance in frailty and correlations of frailty for twins are similar in the data from all three countries is accepted. The estimate of narrow-sense heritability in frailty is about 0.5. The age trajectories of individual hazards are evaluated for all three populations of twins and both sexes. The results of our analysis confirm the presence of genetic influences on individual frailty and longevity. They also suggest that the mechanism of these genetic influences may be similar for the three Scandinavian countries. Furthermore, results indicate that the increase in individual hazard with age is more rapid than predicted by traditional demographic life tables.

The Danish Twin Register.

BACKGROUND: Population based twin registers represent a valuable tool for genetic epidemiological research, since twin studies aim at separating the effect of genes and environment for complex traits. The Danish Twin Register's history, size, ascertainment and completeness of data, as well as data accessibility and availability are described. RESULTS: The Danish Twin Register comprises 14,051 twin pairs born 1870-1930, representing all twins surviving to age six years, and 20,888 twin pairs born 1953-1982, representing 75% of those born 1953-1967 and 95% of those born 1968-1982. The birth cohorts 1931-1952 og 1983-1993 are being ascertained at the moment. The register is available for research given certain conditions are fulfilled. CONCLUSION: This register will in a few years be the most comprehensive twin register in the world. It is a very valuable Danish research resource.

[Mortality among twins after the age of six: the programming hypothesis versus the twin-method]. / Mortalitet blandt tvillinger efter seksårsalderen: programmeringshypotesen versus tvillingmetoden.

According to the foetal-origins hypothesis the risk of adult morbidity and mortality is heightened by intrauterine growth retardation. Twins, and in particular monozygotic twins, experience growth retardation in utero. A total of 8495 twin individuals born 1870-1900 in Denmark were followed through 1991 and death rates were calculated on a cohort basis. Deaths rates for twins and the general population were not significantly different except for females aged 60-89: mortality for female twins in this age group was 1.14 times (SE 0.03) higher than the general population. Female dizygotic twins experienced death rates 1.77 times (SE 0.18) higher than monozygotic twins at ages 30-59. Otherwise, mortality for monozygotic and dizygotic twins did not consistently differ after age six. The findings in the present study suggest that the foetal-origins hypothesis is not true for the intrauterine growth retardation experienced by twins.

Cord blood immunoglobulin E in like-sexed monozygotic and dizygotic twins.

Genetic and environmental factors have been implicated in the etiology of atopy and of serum IgE levels. In order to eliminate post-natal environmental influences we measured IgE in cord blood (CB-IgE) from a cohort of unselected, like-sexed twins. IgE determination was performed with a sensitive radioimmunoassay with a detection limit of 0.01 kU/l. Samples with contamination by maternal blood were identified by IgA determination and excluded. CB-IgE was evaluated in 29 monozygotic (MZ) and 28 dizygotic (DZ) twin pairs. The means and variances for IgE values were comparable for MZ and DZ twins when sex was controlled for. Placental anatomy (MZ twins with mono- and dichorial placenta and DZ twins with one or two placentae) had no significant influence on the IgE levels. In an analysis of variance with sub-sampling the among-pair, within-pair and analytical variance components were calculated. The analytical variance was well below the biological variances. Biometrical analysis showed that the best model by Akaike Information Criteria was a model including only additive genetic and non-shared environmental factors. With this model the heritability estimate was 0.8. These data suggest that the majority of the variation in CB-IgE is accounted for by genetic factors, but a substantial effect of a common environment cannot be excluded with the present sample size.