Henrik Frederiksen

Age- and Sex-differences in the Validity of Questionnaire-based Zygosity in Twins.

Questionnaire-based zygosity assessment in twins has generally been found to be valid. In this report we evaluate sex- and age-differences in the validity of such questionnaire-based classification when using the four questions that have been the basis of zygosity assessment in The Danish Twin Registry for half a century. Three hundred and forty-two male and 531 female twin pairs were zygosity diagnosed using genetic markers and the results compared with the original questionnaire based classification. We found significant differences in the accuracy of questionnaire based zygosity diagnosis when stratifying the data for sex as well as age: males and monozygotic having the highest misclassification. However, even in the group with the highest misclassification rate the frequency was less than 8%. The overall misclassification rate was only 4%, with a clear tendency towards a higher proportion of misclassified monozygotic than dizygotic twins. The results demonstrate that questionnaire based zygosity diagnosis can still be regarded as a valid and valuable classification method for most purposes.

Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study

Patients with chronic myeloproliferative neoplasms, including essential thrombocythemia (ET), polycythemia vera (PV), and chronic myeloid leukemia (CML), are at increased risk of new hematologic malignancies, but their risk of nonhematologic malignancies remains unknown. In the present study, we assessed the risk of both types of malignancies after an ET, PV, or CML diagnosis. We linked 2 population-based nationwide registries, the Danish National Registry of Patients, covering all Danish hospitals and the Danish Cancer Registry, and assessed subsequent cancer risk in a cohort of all 7229 patients diagnosed with a chronic myeloproliferative neoplasm during 1977-2008. We compared the incidence of subsequent cancer in this cohort with that expected on the basis of cancer incidence in the general population (standardized incidence ratio). Overall, ET, PV, and CML patients were at increased risk of developing both new hematologic and nonhematologic cancers. The standardized incidence ratio for developing a nonhematologic cancer was 1.2 (95% confidence interval [95% CI]): 1.0-1.4) for patients with ET, 1.4 (95% CI: 1.3-1.5) for patients with PV, and 1.6 (95% CI: 1.3-2.0) for patients with CML. We conclude that patients with chronic myeloproliferative neoplasms are at increased risk of developing a new malignant disease.

Genetic and Environmental Influences on Self-Reported Reduced Hearing in the Old and Oldest Old

OBJECTIVES: The aim of the present twin study was to estimate the relative importance of genetic and environmental factors in variation in self‐reported reduced hearing among the old and the oldest old.

High concordance for essential tremor in monozygotic twins of old age

Objective: To assess the relative contribution of genetic and environmental factors for the etiology of essential tremor (ET) and to explore the effect of different diagnostic criteria. Methods: A total of 2,448 twins of the Danish twin registry aged 70 years or more were screened for ET by an interview and an Archimedes spiral test. All twin pairs (n = 162) with a positive screening test of at least one of the twins were recontacted and 218 individuals (109 pairs) were interviewed and examined by a movement disorder specialist. The consensus criteria of the Tremor Investigation Group were applied to diagnose ET. Results: Twenty-nine twins fulfilled the criteria of definite, 7 of probable, and 56 of possible ET. The probandwise concordance rate for the broadest definition of ET was 77% for monozygotic twins (MZ) and 59% for dizygotic twins (DZ). However, in an analysis restricted to cases of probable and definite ET, the concordance rates were 93% and 29%. The heritability for the liability to ET ranged from 93% to 99% using a general population prevalence of 1.2% for white 70+-year-olds. The inclusion of probable and exclusion of possible cases in the diagnosis of ET produced the highest concordance rates. Conclusion: The high concordance among MZ twins of very old age in this first population-based twin study of ET suggests that a disease phenotype consisting of definite and probable ET has a high heritability and hence is a good candidate for a phenotype to be used in linkage studies.

Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia

In this study, we report the results from the largest cohort to date of newly diagnosed adult immune thrombocytopenia patients randomized to treatment with dexamethasone alone or in combination with rituximab. Eligible were patients with platelet counts ≤25×10(9)/L or ≤50×10(9)/L with bleeding symptoms. A total of 133 patients were randomly assigned to either dexamethasone 40 mg/day for 4 days (n = 71) or in combination with rituximab 375 mg/m(2) weekly for 4 weeks (n = 62). Patients were allowed supplemental dexamethasone every 1 to 4 weeks for up to 6 cycles. Our primary end point, sustained response (ie, platelets ≥50×10(9)/L) at 6 months follow-up, was reached in 58% of patients in the rituximab + dexamethasone group vs 37% in the dexamethasone group (P = .02). The median follow-up time was 922 days. We found longer time to relapse (P = .03) and longer time to rescue treatment (P = .007) in the rituximab + dexamethasone group. There was an increased incidence of grade 3 to 4 adverse events in the rituximab + dexamethasone group (P = .04). In conclusion, rituximab + dexamethasone induced higher response rates and longer time to relapse than dexamethasone alone. This study is registered at http://clinicaltrials.gov as NCT00909077.

Nordic MCL3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma

The main objective of the MCL3 study was to improve outcome for patients not in complete remission (CR) before transplant by adding (90)Y-ibritumomab-tiuxetan (Zevalin) to the high-dose regimen. One hundred sixty untreated, stage II-IV mantle cell lymphoma patients <66 years received rituximab (R)-maxi-CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) alternating with R-high-dose cytarabine (6 cycles total), followed by high-dose BEAM/C (bis-chloroethylnitrosourea, etoposide, cytarabine, and melphalan or cyclophosphamide) and autologous stem cell transplantation from 2005 to 2009. Zevalin (0.4 mCi/kg) was given to responders not in CR before transplant. Overall response rate pretransplant was 97%. The outcome did not differ from that of the historic control: the MCL2 trial with similar treatment except for Zevalin. Overall survival (OS), event-free survival (EFS), and progression-free survival (PFS) at 4 years were 78%, 62%, and 71%, respectively. For responding non-CR patients who received Zevalin, duration of response was shorter than for the CR group. Inferior PFS, EFS, and OS were predicted by positron emission tomography (PET) positivity pretransplant and detectable minimal residual disease (MRD) after transplant. In conclusion, positive PET and MRD were strong predictors of outcome. Intensification with Zevalin may be too late to improve the outcome of patients not in CR before transplant. This trial was registered at www.clinicaltrials.gov as #NCT00514475.

The influence of genetic factors on physical functioning and exercise in second half of life

During the past decades, a number of studies of families and twins in particular have assessed the relative contribution of genetic and environmental factors to traits reflecting various aspects of physical functioning: maximal O2 uptake, muscular endurance, muscular strength, muscle cross sectional area, flexibility, and trainability. Although the estimate of the size of the genetic component differs between the various studies, they point towards a moderate to substantial genetic influence on these phenotypes. Most of the studies have used only young and healthy study subjects, although in recent years phenotypes of particular importance to the elderly and the oldest‐old (e.g., activities‐of‐daily living abilities) have also been shown to have substantial genetic component. Furthermore, behavioural studies have also revealed a genetic contribution to the disposition to level of leisure time physical activity. At present, there is still a few association studies on specific genetic variants, and the results have either been inconsistent or failed to show an association with physical functioning. Therefore, the mechanisms through which the genetic influence is expressed, is still an enigma. Here, we summarise the evidence currently available for a genetic influence on physical functioning and disposition to leisure time physical activity with a focus on recent Danish twin data.

Genetic and environmental contributions to back pain in old age: a study of 2,108 danish twins aged 70 and older.

Study Design. Self-reported 1-month prevalence of back pain in older twins assessed at intake in a population-based longitudinal survey. Objectives. To determine the relative contribution of genetic and environmental factors to back pain in old age. Summary of Background Data. To date, genetic contributions to back pain in old age have not been assessed, to the authors’ best knowledge. Methods. Interview data given at entry into a nationwide cohort-sequential population-based survey of Danish twins aged 70 years and older in 1995, 1997, 1999, and 2001 form the basis of this analysis. Analysis of twin similarity was estimated using probandwise concordance rates, odds ratios, and tetrachoric correlations for back pain. Heritability (proportion of the population variance attributable to genetic variation) was estimated by bivariate probit estimation and adjusted for known significant environmental factors. Odds ratios for known environmental effects were estimated after controlling for age, sex, and genetic effects. Results. Modest and nonsignificant differences between monozygotic and dizygotic twin pairs were found for probandwise concordance rates, odds ratios, and tet-rachoric correlations for both men and women. In the bivariate probit estimation, a current or previous diagnosis of osteoporosis, degenerative joint disease, or lumbar disc prolapse was found to significantly affect the risk of back pain. Additive genetic effects explained approximately one fourth of the liability to report back pain in men and none of the occurrence in women. Individual environmental effects were found to explain roughly 75% of the occurrence of back pain in men and 100% in women. Conclusions. Additive genetic effects are modest contributors to back pain in older men but not in women. A current or previous medical diagnosis of osteoporosis, degenerative joint disease, or lumbar disc prolapse is-strongly associated with back pain, also when genetic factors are controlled for. Because of inherent methodologic issues, this estimate of the genetic influence on back pain in old age is probably conservative.

Angiotensin I-Converting Enzyme (ACE) Gene Polymorphism in Relation to Physical Performance, Cognition and Survival—A Follow-up Study of Elderly Danish Twins

PURPOSE Studies of younger individuals have suggested an association between ACE genotype and physical and cognitive performance. Using a longitudinal study of elderly twins we studied the association between ACE genotype and physical and cognitive functioning and survival in old age. METHODS Participants were 684 twins aged 73+ years from the 1997 and 1999 surveys of the Longitudinal Study of Aging Danish Twins. Cognitive skills were assessed by the MMSE, while physical abilities were determined through self-report in 1997 and through both self-report and measurement of performance in two physical tasks in 1999. Survival status was obtained through linkage with a national death register. RESULTS Neither physical nor cognitive performance was associated with ACE genotype at baseline in 1997, or at follow-up in 1999. For participants in both surveys longitudinal changes in these skills did not depend on ACE genotype. The relative risk of dying was increased in II compared with the DI and DD genotype with relative risks of 1.6 (95 percent confidence intervals 1.1-2.5) and 1.3 (0.8-2.1), respectively. CONCLUSION We found no substantial effects of ACE genotype on physical and cognitive performance, or rate of change among elderly. Persons with the D allele may have a lower mortality at older ages.

Age trajectories of genetic variance in physical functioning: a longitudinal study of Danish twins aged 70 years and older.

Genetic-evolutionary theories of aging predict that the genetic variance for fitness traits increases with age, while epidemiological-gerontological theories predict an increase in the environmental variance for most traits. In this study we examine the age trajectories of the genetic and environmental variance in physical functioning in a sample of 4731 Danish twins aged 70+ who are being followed longitudinally every second year with up to four assessments completed. A biometric growth model (Neale and McArdle, 2000) was applied to a validated physical ability score. The model included an overall level effect, a rate of linear change effect, and residual effects. The best-fitting model was a sex-specific model including additive genetic and nonshared environmental factors affecting level and rate of change and only nonshared environmental factors affecting the wave-specific levels. For both sexes there is an approximate doubling of both the total variance and the genetic variance in the physical ability score over the four waves and, hence, a rather stable heritability. However, the heritability is approximately .10 for males and .30 for females in all four waves. The heritability of level and slope showed a similar pattern: .11–14 in males and .35–.39 in females. The increase in both additive genetic variance and environmental variance is in agreement with genetic-evolutionary and epidemiological-gerontological theories of aging, respectively. The present study suggests that overall level of strength may be a better phenotype for future molecular genetic studies on physical functioning in the elderly than rate of change, because rate of change is vulnerable to sample attrition due to mortality and dropout and because four waves were needed to be able to detect a heritability for rate of change of the same magnitude as the heritability for level of physical functioning.