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Background: Central nervous system (CNS) tumors are a heterogeneous group of tumors that include several aggressive malignancies with a high mortality rate. This study aimed to evaluate the familial relative risk of CNS tumors in family members of early-onset index cases (probands) in and between diffuse glioma, non-diffuse glioma, meningioma, and other CNS tumors., Methods: We retrieved tumor data from the Finnish cancer registry and familial relationships data from the population information system. We ascertained 5408 probands diagnosed with primary CNS tumors (age ≤40 years) between 1970 and 2012 in Finland. We report the standardized incidence ratios as a measure of familial aggregation using Poisson regression., Results: The risk of early-onset diffuse glioma increased among siblings of probands with the same tumor [SIR 3.85, 95% confidence interval (CI): 1.66-7.59], with association mainly returning to grade 2-3 diffuse gliomas. Early-onset other CNS tumors were associated with an increased risk of other CNS tumors, early-onset meningioma, and late-onset diffuse glioma in 1st-degree relatives. The elevated risk of other CNS tumors was largely caused by schwannomas (SIR 59.44, 95% CI: 27.18-112.84 for 1st-degree relatives) and associated with neurofibromatosis. No tumor syndrome was associated with an increased risk of diffuse gliomas., Conclusions: The early onset of grade 2-3 diffuse gliomas is associated with an increased risk of similar tumor entities. Early-onset schwannomas dramatically increase CNS tumor risk with a broader tumor-type profile. In future studies, it would be important to identify the underlying shared hereditary factors that contribute to the development of familial diffuse gliomas., Competing Interests: No conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Study Question: Does the probability of a live birth after fresh IVF/ICSI cycles with autologous oocytes differ in early onset female cancer survivors compared to their siblings?, Summary Answer: The probability of a live birth was similar in female cancer survivors and siblings after four fresh IVF/ICSI cycles., What Is Known Already: Fertility preservation strategies are rapidly being developed to help female cancer patients who wish to have children later. However, there are only a few studies available on fertility treatments and following live births in female cancer survivors before fertility preservation strategies became available. In one of them, the probability of a live birth was reduced after assisted reproductive technology with autologous oocytes in cancer survivors compared to siblings., Study Design, Size, Duration: In this retrospective, register-based study, data from Finnish registers on cancer, birth and prescribed medications were merged to identify 8944 female cancer survivors (diagnosed with cancer between 1953 and 2012 at the age of 0-40 years) and 9848 female siblings of survivors eligible for IVF/ICSI treatments between January 1993 and December 2012., Participants/materials, Setting, Methods: Fresh IVF/ICSI cycles and following live birth rates (LBRs) within 22-48 weeks in cancer survivors and siblings at the age of 20-41 years were identified. A binomial regression model with log-link function was used to calculate risk ratio (RR) for live births after fresh IVF/ICSI cycles in survivors compared to siblings, adjusting for attained age and calendar time. A Poisson regression model was used to estimate incidence rate ratios (IRRs) for an IVF/ICSI treatment, as well as overall live births, including both pregnancies after fertility treatments and spontaneous pregnancies, in survivors compared to siblings., Main Results and the Role of Chance: We observed an overall decreased LBR, irrespective of IVF/ICSI treatments, in cancer survivors compared to siblings (IRR 0.68, 95% CI 0.64-0.71). All in all, 179 (2.0%) survivors and 230 (2.3%) siblings were prescribed fertility drugs for IVF/ICSI treatments (IRR 0.72, 95% CI 0.62-0.84). For the first fresh IVF/ICSI cycle, the LBR was 17.2% among survivors and 15.7% among siblings (RR 1.13, 95% CI 0.72-1.87). The mean LBR after four fresh IVF/ICSI cycles was not statistically different in survivors compared to siblings., Limitations, Reasons for Caution: In this study, only IVF/ICSI treatments with autologous oocytes were included. The probability of a live birth after a frozen embryo transfer or oocyte donation could not be evaluated in this study. Information on miscarriages, extrauterine pregnancies or termination of pregnancies was not available., Wider Implications of the Findings: For those early onset cancer survivors, who received IVF/ICSI treatments, the probability of live birth was not different from siblings who received IVF/ICSI treatments. However, an overall decreased LBR, irrespective of IVF/ICSI treatments, was observed in cancer survivors compared to siblings, indicating that cancer survivors receiving IVF/ICSI treatments in our study consisted of a selected group with at least a moderate ovarian reserve., Study Funding/competing Interest(s): This study was supported by a grant from the Cancer Foundation (Finland) (grant number 130079) and by a grant from LähiTapiola. The authors have no potential conflicts of interest., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: We assessed population-level changes in glioblastoma survival between 2000 and 2013 in Finland, with focus on elderly patients (>70 y) in order to assess if changes in treatment of glioblastoma are reflected also in population-based survival rates., Methods: We identified all patients (age ≥18 y) from the Finnish Cancer Registry (FCR) with a histopathological diagnosis of primary glioblastoma in 2000-2013. Patients were followed up until December 2015. The accuracy of register-based search of glioblastoma patients was internally validated. We report age-standardized relative survival ratios and relative excess risks (RERs) of death in 2000-2006 (pre-period) and 2007-2013 (post-period)., Results: We identified 2045 glioblastoma patients from the FCR. The accuracy of the FCR-based search was 97%. Median age was 63.3 years, and 42% were women. Incidence increased on average by 1.6% (P = 0.004) and median age by 0.4 years per calendar year. Between the pre- and post-periods, the proportion of patients >70 years increased from 24% to 27%. In >70-year-old patients, the median survival time increased from 3.6 months in 2000-2006 to 4.5 months in 2007-2013 (RER 0.82, 95% CI: 0.68-0.98). In ≤70-year-old patients, the median survival time increased from 9.3 months in 2000-2006 to 11.7 months in 2007-2013 (RER 0.74, 95% CI: 0.67-0.82)., Conclusion: Despite the increased proportion of elderly glioblastoma patients, population-level survival of glioblastoma patients has improved since the year 2000. However, increasing incidence, increasing age of patients, and poor survival in elderly are alarming, and future studies should perhaps focus more on elderly., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Twin studies have been adopted for decades to disentangle the relative genetic and environmental contributions for a wide range of traits. However, heritability estimation based on the classical twin models does not take into account dynamic behavior of the variance components over age. Varying variance of the genetic component over age can imply the existence of gene-environment (G×E) interactions that general genome-wide association studies (GWAS) fail to capture, which may lead to the inconsistency of heritability estimates between twin design and GWAS. Existing parametricG×Einteraction models for twin studies are limited by assuming a linear or quadratic form of the variance curves with respect to a moderator that can, however, be overly restricted in reality. Here we propose spline-based approaches to explore the variance curves of the genetic and environmental components. We choose the additive genetic, common, and unique environmental variance components (ACE) model as the starting point. We treat the component variances as variance functions with respect to age modeled by B-splines or P-splines. We develop an empirical Bayes method to estimate the variance curves together with their confidence bands and provide an R package for public use. Our simulations demonstrate that the proposed methods accurately capture dynamic behavior of the component variances in terms of mean square errors with a data set of >10,000 twin pairs. Using the proposed methods as an alternative and major extension to the classical twin models, our analyses with a large-scale Finnish twin data set (19,510 MZ twins and 27,312 DZ same-sex twins) discover that the variances of the A, C, and E components for body mass index (BMI) change substantially across life span in different patterns and the heritability of BMI drops to ∼50% after middle age. The results further indicate that the decline of heritability is due to increasing unique environmental variance, which provides more insights into age-specific heritability of BMI and evidence ofG×Einteractions. These findings highlight the fundamental importance and implication of the proposed models in facilitating twin studies to investigate the heritability specific to age and other modifying factors., (Copyright © 2016 by the Genetics Society of America.)

Introduction: The role of the nicotinic acetylcholine receptor gene cluster on chromosome 15q24-25 in the etiology of nicotine dependence (ND) is still being defined. In this study, we included all 15 tagging single nucleotide polymorphisms (SNPs) within the CHRNA5-CHRNA3-CHRNB4 cluster and tested associations with 30 smoking-related phenotypes., Methods: The study sample was ascertained from the Finnish Twin Cohort study. Twin pairs born 1938-1957 and concordant for a history of cigarette smoking were recruited along with their family members (mainly siblings), as part of the Nicotine Addiction Genetics consortium. The study sample consisted of 1,428 individuals (59% males) from 735 families, with mean age 55.6 years., Results: We detected multiple novel associations for ND. DSM-IV ND symptoms associated significantly with the proxy SNP Locus 1 (rs2036527, p = .000009) and Locus 2 (rs578776, p = .0001) and tolerance factor of the Nicotine Dependence Syndrome Scale (NDSS) showed suggestive association to rs11636753 (p = .0059), rs11634351 (p = .0069), and rs1948 (p = .0071) in CHRNB4. Furthermore, we report significant association with DSM-IV ND diagnosis (rs2036527, p = .0003) for the first time in a Caucasian population. Several SNPs indicated suggestive association for traits related to ages at smoking initiation. Also, rs11636753 in CHRNB4 showed suggestive association with regular drinking (p = .0029) and the comorbidity of depression and ND (p = .0034)., Conclusions: We demonstrate novel associations of DSM-IV ND symptoms and the NDSS tolerance subscale. Our results confirm and extend association findings for other ND measures. We show pleiotropic effects of this gene cluster on multiple measures of ND and also regular drinking and the comorbidity of ND and depression.

Introduction: To obtain reliable information on nicotine and drug use through a population-based study, the prevalence of nicotine use in deceased young adults was studied in the Finnish postmortem toxicology database for a 3-year period. The nicotine user and non-nicotine user groups were compared by alcohol, drug, and drug-of-abuse findings and by the manner of death., Methods: Nicotine users were identified based on detection of nicotine, cotinine, and/or trans-3'-hydroxycotinine in urine from a population-based sample of deceased young adults aged 15-34 years at the time of death (n = 1,623, ∼60% of all fatalities). Background information from case referrals was used to distinguish the abuse of medicines from their therapeutic use. The manner of death was taken from death certificates., Results: Nicotine use was more common in young adults (75%) than among all cases in the database (55%). There were twice as many ethanol-positive cases in nicotine users (60%) than in non-nicotine users (30%). Nicotine use was common (70%-79%) among individuals on antipsychotics, antidepressants, anxiolytics, and/or hypnotics and sedatives. The proportion of nicotine users was also high among the drugs-of-abuse positive cases (85%). There were fewer deaths that were classified as natural in the nicotine users group., Conclusions: Among deceased young adults, nicotine use was two to three times as common as has been estimated for the corresponding living population (20%-30%). Nicotine use was also strongly associated with substance abuse and mental illnesses requiring pharmacotherapy. This group of young adults usually cannot be reached by traditional health surveys.

Introduction: Genetic effects contribute to individual differences in smoking behavior. Persistence to smoke despite known harmful health effects is mostly driven by nicotine addiction. As the physiological effects of nicotine are mediated by nicotinic acetylcholine receptors (nAChRs), we aimed at examining whether single nucleotide polymorphisms (SNPs) residing in nAChR subunit (CHRN) genes, other than CHRNA3/CHRNA5/CHRNB4 gene cluster previously showing association in our sample, are associated with smoking quantity or serum cotinine levels., Methods: The study sample consisted of 485 Finnish adult daily smokers (age 30-75 years, 59% men) assessed for the number of cigarettes smoked per day (CPD) and serum cotinine level. We first studied SNPs residing on selected nAChR subunit genes (CHRNA2, CHRNA4, CHRNA6/CHRNB3, CHRNA7, CHRNA9, CHRNA10, CHRNB2, CHRNG/CHRND) genotyped within a genome-wide association study for single SNP and multiple SNP associations by ordinal regression. Next, we explored individual haplotype associations using sliding window technique., Results: At one of the 8 loci studied, CHRNG/CHRND (chr2), single SNP (rs1190452), multiple SNP, and 2-SNP haplotype analyses (SNPs rs4973539-rs1190452) all showed statistically significant association with cotinine level. The median cotinine levels varied between the 2-SNP haplotypes from 220 ng/ml (AA haplotype) to 249 ng/ml (AG haplotype). We did not observe significant associations with CPD., Conclusions: These results provide further evidence that the γ-δ nAChR subunit gene region is associated with cotinine levels but not with the number of CPD, illustrating the usefulness of biomarkers in genetic analyses.

Seasonal patterns in the incidence of insulin-dependent diabetes based on 2,062 cases diagnosed at age 14 years or under in Finland are described for the years 1987-1992. Seasonal patterns were estimated presenting the data as short Fourier series up to three harmonics together with a possible linear trend. This method allows an arbitrary shape for the seasonal effect. Likelihood ratio tests and Akaike's information criterion were used to determine the number of harmonics necessary to model the seasonal pattern and to test differences among age- and sex-specific subgroups in the population. Seasonal patterns in incidence were compared between sexes and between the three 5-year age groups with each controlling for the other's effect. A significant seasonal pattern in the incidence of insulin-dependent diabetes was found for the sexes combined and for two age groups (0-9 and 10-14 years). A statistically significant seasonal pattern could be confirmed for males, but not for females. During a calendar year, one cycle with a decreased incidence of insulin-dependent diabetes in June was found among younger boys. Among older boys, there were two distinct cycles with a decreased incidence, the first in June and the second during November-December. The most visible seasonal pattern was a lower number of cases diagnosed in June, while during the rest of the year the incidence remained relatively stable and high. The average annual incidence was 35.6 per 100,000 persons without any upward peaks.

Background: In Finland, the incidence of insulin-dependent diabetes mellitus (IDDM) in children aged < 15 years is the highest in the world. The aim of this study was to determine the temporal variation in incidence and the age distribution at diagnosis of IDDM., Subjects and Methods: Data on incidence of IDDM in Finland nationwide were obtained from two sources: the Central Drug Registry for the years 1965-1986 (6195 IDDM cases) and the prospective IDDM registry for the years 1987-1992 (2062 IDDM cases). The annual incidence rates were calculated per 100,000 population. The increase in incidence from 1965 to 1992 was estimated by fitting the linear regression with the annual incidence data., Results: The overall incidence of IDDM between 1987 and 1992 was 36 per 100,000/year. During 1965-1992 the increase was almost linear. The regression-based change in incidence was 2.8% per year. In the 1970s the increase in incidence was steepest in 5-9 year olds and since the mid-1980s in those < 5 years old at diagnosis., Conclusions: The incidence of IDDM in Finnish children seems to increase further. During the last decades the increase in incidence has been almost linear with occasional peaks. The age-at-diagnosis of IDDM has been moving towards the younger ages, and differences in incidence between age groups have now almost disappeared among Finnish children aged 1-14 years.

Background: Population-based studies of the association between smoking and Chlamydia pneumoniae seropositivity do not exist. The role of smoking in the association between C. pneumoniae seropositivity and coronary artery disease (CAD) suggested by several studies has been debated. The aim of this study was to determine the relationship between smoking habits and C. pneumoniae IgG antibody titres in a middle-aged population. We also wanted to find out whether the difference in smoking habits between the sexes explains the higher C. pneumoniae antibody prevalence among men compared with women., Results: After controlling for the effect of smoking, the risk of C. pneumoniae seropositivity remained 1.4 times higher in men than in women. In men, the estimated risk for C. pneumoniae seropositivity (titre > or = 1:16) was significant only for smokers (adjusted odds ratio [OR] = 1.4). The adjusted OR for high seropositivity (titre > or = 1:128) was 1.5 for smokers and 1.7 for ex-smokers. The risk for women was similar to that for men., Conclusions: The results provide evidence of an association between smoking and C. pneumoniae seropositivity in the general population. The higher prevalence of smoking in men does not explain the C. pneumoniae antibody prevalence in men compared with women.

Chlamydia pneumonia IgG antibody prevalence was examined in a representative sample (2342 subjects) of the population aged 25-59 years in south-western and eastern Finland in 1982 and 1987. Microimmunofluorescence was used to measure IgG antibodies. Prevalence of C. pneumoniae was modelled using the GLIM statistical package assuming that the prevalence had a binomial distribution. The prevalence was assumed to be a function of the year, subjects' gender, age and place of residence. The effect of the year on the prevalence was significant in both regions (P < 0.05 in the south-west and P < 0.001 in the east). In each year the prevalence was higher in the south-west than in the east and it increased between 1982 and 1987 from 55% to 63% in the south-west and from 41% to 59% in the east. The prevalence increased with age, but the age-related antibody pattern was different between sexes. The highest prevalence was found in men aged 49-59 years. The different increase in prevalence with age in the south-western and the eastern parts of the country indicates that the outbreaks of infection were not related. The endemic level of C. pneumoniae infection in the south-west is consistently higher than in the east, or there was an outbreak of C. pneumoniae infection in both the years we examined. Thus it is more likely that the high prevalence in south-western Finland was connected more with the epidemics reported elsewhere in Scandinavia in the same years than with the occurrence of C. pneumoniae infection in eastern Finland.

The prevalence of diabetes mellitus and impaired glucose tolerance (IGT) was determined in a random sample of the population aged 45-64 years in three areas of Finland. The two-hour oral glucose tolerance test was repeated in subjects whose first test suggested abnormal glucose tolerance. In the final classification, based on the results of the two tests, the age-standardized prevalence of diabetes, according to the WHO criteria was 5.7% (95% confidence interval (CI): 4.3-7.1) in men and 4.6% (95% CI: 3.6-5.0) in women. The prevalence of IGT was 3.1% (95% CI: 2.1-4.1) in men and 5.1% (95% CI: 3.9-6.3) in women. Among those aged 55-64 years the prevalence was 6.9% in men and 7.5% in women. The prevalence of diabetes and IGT were not different between the three areas. The age-specific mean values of fasting and two-hour blood concentrations and the 90th percentiles of the blood glucose distributions were also not different between the areas. The prevalence of IGT and diabetes increased with age more steeply among women than men. The median of fasting blood glucose did not change, but the 90th percentile increased with increasing age. The entire distribution of two-hour blood glucose shifted towards higher values with ageing, but the major increase was seen for the 95th percentile. The majority of the diabetic subjects were aware of their condition. The awareness was better among men than women.