The Swedish Family-Cancer Database: Update, Application to Colorectal Cancer and Clinical Relevance

The Swedish Family-Cancer Database has been used for almost 10 years in the study of familial risks at all common sites. In the present paper we describe some main features of version VI of this Database, assembled in 2004. This update included all Swedes born in 1932 and later (offspring) with their biological parents, a total of 10.5 million individuals. Cancer cases were retrieved from the Swedish Cancer Registry from 1958-2002, including over 1.2 million first and multiple primary cancers and in situ tumours. Compared to previous versions, only 6.0% of deceased offspring with a cancer diagnosis lack any parental information. We show one application of the Database in the study of familial risks in colorectal adenocarcinoma, with defined age-group and anatomic site specific analyses. Familial standardized incidence ratios (SIRs) were determined for offspring when parents or sibling were diagnosed with colon or rectal cancer. As a novel finding it was shown that risks for siblings were higher than those for offspring of affected parents. The excess risk was limited to colon cancer and particularly to right-sided colon cancer. The SIRs for colon cancer in age matched populations were 2.58 when parents were probands and 3.81 when siblings were probands; for right-sided colon cancer the SIRs were 3.66 and 7.53, respectively. Thus the familial excess (SIR-1.00) was more than two fold higher for right-sided colon cancer. Colon and rectal cancers appeared to be distinguished between high-penetrant and recessive conditions that only affect the colon, whereas low-penetrant familial effects are shared by the two sites. Epidemiological studies can be used to generate clinical estimates for familial risk, conditioned on numbers of affected family members and their ages of onset. Useful risk estimates have been developed for familial breast and prostate cancers. Reliable risk estimates for other cancers should also be seriously considered for routine clinical recommendations, because practically all cancers show a familial effect and the risks are high for some of the rare neoplasms. The implementation of a unified management plan for familial cancers at large will be a major challenge to the clinical genetic counselling community

The updated Swedish family-cancer database used to assess familial risks of prostate cancer during rapidly increasing incidence

The Swedish Family-Cancer Database has been used for some 10 years in the study of familial risks at all common sites. In the present paper we describe some of the main features of version VII of this Database, assembled in year 2006. This update included all residents in Sweden born or immigrated in 1932 and later (offspring) with their biological parents, a total of 11.5 million individuals. Cancer cases were retrieved from the Swedish Cancer Registry from years 1958 to 2004, including over 1.2 million first and multiple primary cancers and in situ tumours. We show one application of the Database in the study of familial risks in prostate cancer, with special reference to the modification of familial risk at the time of about 50% increase in incidence due to prostate specific antigen (PSA) screening. The familial risks for prostate cancer were 1.92 for sons of affected fathers, 3.03 for brothers and 5.44 for men with an affected father and an affected brother. Familial risk for prostate cancer according to the time since the first family member was diagnosed showed significant increases for two family members being diagnosed in the same year compared to 5+ years apart. Increased surveillance and the availability of PSA screening are the likely reasons for the overestimated familial relative risk shortly after the first diagnosis. This lead time bias should be considered in clinical counselling

A Comparison of Three Methods to Measure Asthma in Epidemiologic Studies: Results from the Danish National Birth Cohort

Asthma is a heterogeneous outcome and how the condition should be measured to best capture clinically relevant disease in epidemiologic studies remains unclear. We compared three methods of measuring asthma in the Danish National Birth Cohort (n>50.000). When the children were 7 years old, the prevalence of asthma was estimated from a self-administered questionnaire using parental report of doctor diagnoses, ICD-10 diagnoses from a population-based hospitalization registry, and data on anti-asthmatic medication from a population-based prescription registry. We assessed the agreement between the methods using kappa statistics. Highest prevalence of asthma was found using the prescription registry (32.2%) followed by the self-report (12.0%) and the hospitalization registry (6.6%). We found a substantial non-overlap between the methods (kappa = 0.21–0.38). When all three methods were combined the asthma prevalence was 3.6%. In conclusion, self-reported asthma, ICD-10 diagnoses from a hospitalization registry and data on anti-asthmatic medication use from a prescription registry lead to different prevalences of asthma in the same cohort of children. The non-overlap between the methods may be due to different abilities of the methods to identify cases with different phenotypes, in which case they should be treated as separate outcomes in future aetiological studies

Maternal vitamin D status and offspring bone fractures:Prospective study over two decades in Aarhus City, Denmark

BACKGROUND:Studies investigating the association between maternal vitamin D status and offspring bone mass measured by dual-energy X-ray absorptiometry (DXA) during childhood have shown conflicting results. PURPOSE:We used occurrence of bone fractures up to the age of 18 as a measure reflecting offspring bone mass and related that to maternal vitamin D status. METHODS:The Danish Fetal Origins 1988 Cohort recruited 965 pregnant women during 1988-89 at their 30th gestation week antenatal midwife visit. A blood sample was drawn and serum was stored, which later was analyzed for the concentration of 25-hydroxyvitamin D (25(OH)D) by the liquid chromatography coupled with a tandem mass spectrometric method (LC-MS/MS). Outcome was diagnosis of first time bone fractures extracted from the Danish National Patient Register. RESULTS:Vitamin D status was available for 850 women. The median (5th-95th percentile) 25(OH)D was 76.2 (23.0-152.1) nmol/l. During follow up 294 children were registered with at least one bone fracture diagnosis. Multivariable Cox regression models using age as the underlying time scale indicated no overall association between maternal vitamin D status and first time bone fractures. However, there was a significantly increased hazard ratio (HR) during childhood for those who had maternal blood drawn in Dec/Jan/Feb compared with Jun/Jul/Aug (HR: 1.75, 95%CI: 1.11-2.74). Adjustment for vitamin D status strengthened this association (1.82, 1.12-2.97), which indicated a potential seasonal impact on offspring fractures independent of maternal vitamin D status. In a sensitivity analysis we found a borderline significant inverse association between continuous concentrations of 25(OH)D and offspring forearm fractures (P = 0.054). CONCLUSION:Overall, our results did not substantiate an association between maternal vitamin D status and offspring bone fractures. Further studies on this subject are needed, but the study populations must be large enough to allow for subdivision of fractures

Dietary glycemic index during pregnancy is associated with biomarkers of the metabolic syndrome in offspring at age 20 years.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Growing evidence indicates that metabolic syndrome is rooted in fetal life with a potential key role of nutrition during pregnancy. The objective of the study was to assess the possible associations between the dietary glycemic index (GI) and glycemic load (GL) during pregnancy and biomarkers of the metabolic syndrome in young adult offspring.Dietary GI and GL were assessed by questionnaires and interviews in gestation week 30 and offspring were clinically examined at the age of 20 years. Analyses based on 428 mother-offspring dyads were adjusted for maternal smoking during pregnancy, height, pre-pregnancy body mass index (BMI), education, energy intake, and the offspring's ambient level of physical activity. In addition, possible confounding by gestational diabetes mellitus was taken into account.Waist circumference, blood pressure, HOMA insulin resistance (HOMA-IR) and plasma levels of fasting glucose, triglycerides, HDL cholesterol, LDL cholesterol, total cholesterol, insulin, and leptin were measured in the offspring.Significant associations were found between dietary GI in pregnancy and HOMA-IR (the relative increase in HOMA-IR per 10 units' GI increase was 1.09 [95% CI: 1.01, 1.16], p = 0.02), insulin (1.09 [95% CI: 1.02, 1.16], p = 0.01) and leptin (1.21 [95% CI: 1.06, 1.38], p = 0.01) in the offspring; whereas no associations were detected for GL.Our data suggests that high dietary GI in pregnancy may affect levels of markers for the metabolic syndrome in young adult offspring in a potentially harmful direction.Danish Council for Strategic Research/ 09-067124 09-063072 2101-06-000

Association Between Maternal Folic Acid Supplementation and Congenital Heart Defects in Offspring in Birth Cohorts From Denmark and Norway

Background: Evidence linking individual‐level maternal folic acid supplementation to offspring risk of congenital heart defects is lacking. We investigated whether folic acid supplementation in early pregnancy reduces offspring risk of heart defects in 2 large birth cohort studies. Methods and Results: Women recruited in early pregnancy within the DNBC (Danish National Birth Cohort), 1996–2003, and MoBa (Norwegian Mother and Child Cohort Study), 2000–2009, were followed until delivery. Information on periconceptional intake of folic acid and other supplements was linked with information on heart defects from national registers. Among 197 123 births, we identified 2247 individuals with heart defects (114/10 000). Periconceptional (4 weeks before through 8 weeks after conception) use of folic acid plus other supplements (54.8%), folic acid only (12.2%), and non–folic acid supplements (5.0%) were compared with no supplement use (28.0%); the adjusted relative risks of heart defects were 0.99 (95% CI, 0.80–1.22), 1.08 (95% CI, 0.93–1.25), and 1.07 (95% CI, 0.97–1.19), respectively. For initiation of folic acid in the preconception period weeks −4 to −1 (33.7%) and the postconception periods 0 to 4 weeks (15.5%), 5 to 8 weeks (17.8%), and 9 to 12 weeks (4.6%), compared with no or late folic acid intake (29.1%), relative risks of heart defect were 1.11 (95% CI, 1.00–1.25), 1.09 (95% CI, 0.95–1.25), 0.98 (95% CI, 0.86–1.12), and 0.97 (95% CI, 0.78–1.20), respectively. Relative risks of severe defects, conotruncal defects, and septal defects showed similar results. Conclusions: Folic acid was not associated with offspring risk of heart defects, including severe defects, conotruncal defects, or septal defects.publishedVersio

Sources and Determinants of Vitamin D Intake in Danish Pregnant Women

Vitamin D deficiency during pregnancy has been associated with the development of several adverse health outcomes, e.g., pre-eclampsia, gestational diabetes mellitus, preterm delivery, low birth weight, birth length, and bone mineral content. The aims of the present study were to estimate the intake and sources of vitamin D in Danish pregnant women and to examine potential determinants of vitamin D intake of the recommended level (10 µg per day). In 68,447 Danish pregnant women the mean ± SD for vitamin D intake was 9.23 ± 5.60 µg per day (diet: 3.56 ± 2.05 µg per day, supplements: 5.67 ± 5.20 µg per day). 67.6% of the women reported use of vitamin D supplements but only 36.9% reported use of vitamin D supplements of at least 10 µg. Supplements were the primary source of vitamin D for the two higher quartiles of total vitamin D intake, with diet being the primary source for the two lower quartiles. Determinants of sufficient total vitamin D intake were: high maternal age, nulliparity, non-smoking, and filling out of the Food Frequency Questionnaire (FFQ) during summer or fall. We propose that clinicians encourage vitamin D supplementation among pregnant women, with special focus on vulnerable groups such as the young, smokers and multiparous women, in order to improve maternal and fetal health both during and after pregnancy

Association between maternal gluten intake and type 1 diabetes in offspring: national prospective cohort study in Denmark.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadTo examine the association between prenatal gluten exposure and offspring risk of type 1 diabetes in humans. National prospective cohort study. National health information registries in Denmark. Pregnant Danish women enrolled into the Danish National Birth Cohort, between January 1996 and October 2002, MAIN OUTCOME MEASURES: Maternal gluten intake, based on maternal consumption of gluten containing foods, was reported in a 360 item food frequency questionnaire at week 25 of pregnancy. Information on type 1 diabetes occurrence in the participants' children, from 1 January 1996 to 31 May 2016, were obtained through registry linkage to the Danish Registry of Childhood and Adolescent Diabetes.Kirsten and Freddy Johansens Foundation March of Dimes Foundation Innovation Fund Denmark Danish Heart Association Sygekassernes Helsefond Danish National Research Foundatio

Associations between maternal physical activity in early and late pregnancy and offspring birth size: remote federated individual level meta-analysis from eight cohort studies.

OBJECTIVE: Evidence on the impact of leisure time physical activity (LTPA) in pregnancy on birth size is inconsistent. We aimed to examine the association between LTPA during early and late pregnancy and newborn anthropometric outcomes. DESIGN: Individual level meta-analysis, which reduces heterogeneity across studies. SETTING: A consortium of eight population-based studies (seven European and one US) comprising 72,694 participants. METHODS: Generalised linear models with consistent inclusion of confounders (gestational age, sex, parity, maternal age, education, ethnicity, BMI, smoking and alcohol intake) were used to test associations between self-reported LTPA at either early (8-18 weeks gestation) or late pregnancy (30+ weeks) and the outcomes. Results were pooled using random effects meta-analyses. MAIN OUTCOME MEASURES: Birth weight, Large-for-gestational age (LGA), macrosomia, small-for-gestational age (SGA), %body fat and ponderal index at birth. RESULTS: Late, but not early, gestation maternal moderate-to-vigorous physical activity (MVPA), vigorous activity and LTPA energy expenditure were modestly inversely associated with BW, LGA, macrosomia and ponderal index, without heterogeneity (all: I-square=0%). For each extra hour/week of MVPA, RR for LGA and macrosomia were 0.97 (95% CI: 0.96, 0.98) and 0.96 (95%CI: 0.94, 0.98) respectively. Associations were only modestly reduced after additional adjustments for maternal BMI and gestational diabetes. No measure of LTPA was associated with risk for SGA. CONCLUSIONS: Physical activity in late, but not early, pregnancy is consistently associated with modestly lower risk of LGA and macrosomia, but not SGA. This article is protected by copyright. All rights reserved.Includes MRC, Wellcome Trust and NIHR