Early life body size and puberty markers as predictors of breast cancer risk later in life: A neural network analysis.

BACKGROUND: The early life factors of birthweight, child weight, height, body mass index (BMI) and pubertal timing are associated with risks of breast cancer. However, the predictive value of these factors in relation to breast cancer is largely unknown. Therefore, using a machine learning approach, we examined whether birthweight, childhood weights, heights, BMIs, and pubertal timing individually and in combination were predictive of breast cancer. METHODS: We used information on birthweight, childhood height and weight, and pubertal timing assessed by the onset of the growth spurt (OGS) from 164,216 girls born 1930-1996 from the Copenhagen School Health Records Register. Of these, 10,002 women were diagnosed with breast cancer during 1977-2019 according to a nationwide breast cancer database. We developed a feed-forward neural network, which was trained and tested on early life body size measures individually and in various combinations. Evaluation metrics were examined to identify the best performing model. RESULTS: The highest area under the receiver operating curve (AUC) was achieved in a model that included birthweight, childhood heights, weights and age at OGS (AUC = 0.600). A model based on childhood heights and weights had a comparable AUC value (AUC = 0.598), whereas a model including only childhood heights had the lowest AUC value (AUC = 0.572). The sensitivity of the models ranged from 0.698 to 0.760 while the precision ranged from 0.071 to 0.076. CONCLUSION: We found that the best performing network was based on birthweight, childhood weights, heights and age at OGS as the input features. Nonetheless, this performance was only slightly better than the model including childhood heights and weights. Further, although the performance of our networks was relatively low, it was similar to those from previous studies including well-established risk factors. As such, our results suggest that childhood body size may add additional value to breast cancer prediction models.

Trajectories of body mass index across the lifecourse and associations with post-menopausal breast cancer by estrogen receptor status.

BACKGROUND: Associations between a high body mass index (BMI) at single timepoints during child- and adulthood and risks of post-menopausal breast cancer are well-established, but associations with BMI across the lifecourse remains largely unknown. Therefore, we examined whether lifecourse BMI trajectories were associated with risks of post-menopausal breast cancer overall and by estrogen receptor (ER) status. METHODS: We included 6698 Danish women born 1930-1946. Information on BMI at ages 6-15 years came from the Copenhagen School Health Records Register, and information on BMI at ages 20, 30, 40, 50 and/or 50-64 years came from the Diet, Cancer and Health cohort. Breast cancer cases (n = 577) were identified in the Danish Breast Cancer Cooperative Group database. Six BMI trajectories were identified using latent class trajectory modelling. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression models. RESULTS: Compared to women with a trajectory characterized by an average BMI gain across life, women with the two trajectories with steep increases in BMI during childhood and adolescence that thereafter largely stabilized, had lower risks of post-menopausal breast cancer and ER-positive tumors. The adjusted HRs for ER-positive tumors were 0.67 (95% CI: 0.47-0.95) and 0.68 (95% CI: 0.46-1.01), respectively. In contrast, women with a trajectory with a low gain in BMI during childhood and adolescence followed by a subsequent steep increase during adulthood, had higher risks of post-menopausal breast cancer and ER-positive tumors when compared to women with an average BMI gain. The adjusted HR for ER-positive tumors was 1.28 (95% CI: 0.98-1.67). CONCLUSIONS: Our findings suggest that the timing of excess gain in BMI across the lifecourse impacts subsequent post-menopausal breast cancer risks. Thus, the BMI development across life is likely useful in the identification of women at increased risks of post-menopausal breast cancer.

Ancient Yersinia pestis genomes lack the virulence-associated YpfΦ prophage present in modern pandemic strains.

Yersinia pestis is the causative agent of at least three major plague pandemics (Justinianic, Medieval and Modern). Previous studies on ancient Y. pestis genomes revealed that several genomic alterations had occurred approximately 5000-3000 years ago and contributed to the remarkable virulence of this pathogen. How a subset of strains evolved to cause the Modern pandemic is less well-understood. Here, we examined the virulence-associated prophage (YpfΦ), which had been postulated to be exclusively present in the genomes of strains associated with the Modern pandemic. The analysis of two new Y. pestis genomes from medieval/early modern Denmark confirmed that the phage is absent from the genome of strains dating to this time period. An extended comparative genome analysis of over 300 strains spanning more than 5000 years showed that the prophage is found in the genomes of modern strains only and suggests an integration into the genome during recent Y. pestis evolution. The phage-encoded Zot protein showed structural homology to a virulence factor of Vibrio cholerae. Similar to modern Y. pestis, we observed phages with a common origin to YpfΦ in individual strains of other bacterial species. Our findings present an updated view on the prevalence of YpfΦ, which might contribute to our understanding of the host spectrum, geographical spread and virulence of Y. pestis responsible for the Modern pandemic.

Heritability and circulating concentrations of pregnancy-associated plasma protein-A and stanniocalcin-2 in elderly monozygotic and dizygotic twins.

Introduction: Pregnancy-associated plasma protein-A (PAPP-A) is an IGF-activating enzyme suggested to influence aging-related diseases. However, knowledge on serum PAPP-A concentration and regulation in elderly subjects is limited. Therefore, we measured serum PAPP-A in elderly same-sex monozygotic (MZ) and dizygotic (DZ) twins, as this allowed us to describe the age-relationship of PAPP-A, and to test the hypothesis that serum PAPP-A concentrations are genetically determined. As PAPP-A is functionally related to stanniocalcin-2 (STC2), an endogenous PAPP-A inhibitor, we included measurements on STC2 as well as IGF-I and IGF-II. Methods: The twin cohort contained 596 subjects (250 MZ twins, 346 DZ twins), whereof 33% were males. The age ranged from 73.2 to 94.3 (mean 78.8) years. Serum was analyzed for PAPP-A, STC2, IGF-I, and IGF-II by commercial immunoassays. Results: In the twin cohort, PAPP-A increased with age (r=0.19; P<0.05), whereas IGF-I decreased (r=-0.12; P<0.05). Neither STC2 nor IGF-II showed any age relationship. When analyzed according to sex, PAPP-A correlated positively with age in males (r=0.18; P<0.05) and females (r=0.25; P<0.01), whereas IGF-I correlated inversely in females only (r=-0.15; P<0.01). Males had higher levels of PAPP-A (29%), STC2 (18%) and IGF-I (19%), whereas serum IGF-II was 28% higher in females (all P<0.001). For all four proteins, within-pair correlations were significantly higher for MZ twins than for DZ twins, and they demonstrated substantial and significant heritability, which after adjustment for age and sex averaged 59% for PAPP-A, 66% for STC2, 58% for IGF-I, and 52% for IGF-II. Discussion: This twin study confirms our hypothesis that the heritability of PAPP-A serum concentrations is substantial, and the same is true for STC2. As regards the age relationship, PAPP-A increases with age, whereas STC2 remains unchanged, thereby supporting the idea that the ability of STC2 to inhibit PAPP-A enzymatic activity decreases with increasing age.

Association of Trauma With Long-Term Risk of Death and Immune-Mediated or Cancer Disease in Same-Sex Twins.

Importance: Immediate consequences of trauma include a rapid and immense activation of the immune system, whereas long-term outcomes include premature death, physical disability, and reduced workability. Objective: To investigate if moderate to severe trauma is associated with long-term increased risk of death or immune-mediated or cancer disease. Design, Setting, and Participants: This registry-based, matched, co-twin control cohort study linked the Danish Twin Registry and the Danish National Patient Registry to identify twin pairs in which 1 twin had been exposed to severe trauma and the other twin had not from 1994 to 2018. The co-twin control design allowed for matching on genetic and environmental factors shared within twin pairs. Exposure: Twin pairs were included if 1 twin had been exposed to moderate to severe trauma and the other twin had not (ie, co-twin). Only twin pairs where both twins were alive 6 months after the trauma event were included. Main Outcome and Measure: Twin pairs were followed up from 6 months after trauma until 1 twin experienced the primary composite outcome of death or 1 of 24 predefined immune-mediated or cancer diseases or end of follow-up. Cox proportional hazards regression was used for intrapair analyses of the association between trauma and the primary outcome. Results: A total of 3776 twin pairs were included, and 2290 (61%) were disease free prior to outcome analysis and were eligible for the analysis of the primary outcome. The median (IQR) age was 36.4 (25.7-50.2) years. The median (IQR) follow-up time was 8.6 (3.8-14.5) years. Overall, 1268 twin pairs (55%) reached the primary outcome; the twin exposed to trauma was first to experience the outcome in 724 pairs (32%), whereas the co-twin was first in 544 pairs (24%). The hazard ratio for reaching the composite outcome was 1.33 (95% CI, 1.19-1.49) for twins exposed to trauma. Analyses of death or immune-mediated or cancer disease as separate outcomes provided hazard ratios of 1.91 (95% CI, 1.68-2.18) and 1.28 (95% CI, 1.14-1.44), respectively. Conclusion and Relevance: In this study, twins exposed to moderate to severe trauma had significantly increased risk of death or immune-mediated or cancer disease several years after trauma compared with their co-twins.

The association between skeletal lesions and tuberculosis in a pre-antibiotic South African sample.

OBJECTIVE: This study assessed the sensitivity and specificity of skeletal lesions to accurately diagnose TB in a pre-antibiotic South African skeletal sample. MATERIALS: A total of 435 skeletons of individuals who died before 1950 from the Raymond A. Dart Collection of Human Skeletons. 176 died of TB, 109 died of other pulmonary diseases, and 150 died of other causes. METHODS: The presence / absence of 23 skeletal lesions were assessed for differences in frequency between groups. Sensitivities and specificities were calculated and compared to Dangvard Pedersen et al. (2019). RESULTS: Lesions on the ventral surface of thoracic and lumbar vertebral bodies were observed significantly more often in TB and pulmonary cases than in other cause of death group and yielded a 55% probability of a true TB diagnosis, if observed. An association between skeletal lesions and TB was found for rib and vertebral lesions. CONCLUSIONS: The results suggest that even when not documented to have died of TB, TB-related changes are observed in many individuals in a South African skeletal sample, indicating that they may have been infected with the disease. SIGNIFICANCE: The study provides information that can assist palaeopathologists in making inferences about the prevalence of TB in past populations. LIMITATIONS: Sample sizes were small, and the inclusion of a pulmonary disease group may have confounded the results. SUGGESTIONS FOR FURTHER RESEARCH: The selection of a control group without any possible contact with TB may improve the results and should be investigated.

Birthweight, childhood body size, and timing of puberty and risks of breast cancer by menopausal status and tumor receptor subtypes.

BACKGROUND: Associations of birthweight, childhood body size and pubertal timing with breast cancer risks by menopausal status and tumor receptor subtypes are inconclusive. Thus, we investigated these associations in a population-based cohort of Danish women. METHODS: We studied 162,419 women born between 1930 and 1996 from the Copenhagen School Health Records Register. The register includes information on birthweight, measured childhood weights and heights at the age of 7-13 years, and computed ages at the onset of the growth spurt (OGS) and at peak height velocity (PHV). The Danish Breast Cancer Cooperative Group database provided information on breast cancer (n = 7510), including estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2) and menopausal status. Hormone replacement therapy use came from the Danish National Prescription Registry. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox regression. RESULTS: We found that birthweight was not associated with any breast cancer subtypes. While childhood BMI was not statistically significantly associated with ER+ tumors nor consistently with ER- tumors among pre-menopausal women, consistent inverse associations were found among postmenopausal women. At the age of 7 years, the HRs for postmenopausal ER+ and ER- tumors were 0.90 (95% CI 0.87-0.93) and 0.84 (95% CI 0.79-0.91) per BMI z-score, respectively. Similarly, childhood BMI was inversely associated with pre- and postmenopausal HER2- tumors, but not with HER2+ tumors. Childhood height was positively associated with both pre- and postmenopausal ER+ tumors, but not with ER- tumors. At the age of 7 years, the HRs for postmenopausal ER+ and ER- tumors were 1.09 (95% CI 1.06-1.12) and 1.02 (95% CI 0.96-1.09) per height z-score, respectively. In general, childhood height was positively associated with HER2+ and HER2- tumors among pre- and postmenopausal women. Ages at OGS and PHV were not associated with any breast cancer subtypes. CONCLUSIONS: We showed that a high BMI and short stature in childhood are associated with reduced risks of certain breast cancer subtypes. Thus, childhood body composition may play a role in the development of breast cancer.

Reassessing the evidence of a survival advantage in Type 2 diabetes treated with metformin compared with controls without diabetes: a retrospective cohort study.

BACKGROUND: Previous research has suggested that individuals with Type 2 diabetes and initiated on metformin monotherapy present with a survival advantage compared with the general population without diabetes. This finding has generated considerable interest in the prophylactic use of metformin against age-related morbidity. METHODS: Utilizing Danish National Health Registers, we assessed differences in survival associated with metformin monotherapy for Type 2 diabetes compared with no diagnosis of diabetes in both singleton and discordant twin populations between 1996 and 2012. Data were analysed in both nested case-control and matched cohort study designs, with incidence rate ratios (IRRs) and hazard ratios estimated using conditional logistic regression and Cox proportional hazards regression, respectively. RESULTS: In case-control pairs matched on birth year and sex or co-twin (sex, birth year and familial factors), incident Type 2 diabetes with treatment by metformin monotherapy initiation compared with no diagnosis of diabetes was associated with increased mortality in both singletons (IRR = 1.52, 95% CI: 1.37, 1.68) and discordant twin pairs (IRR = 1.90, 95% CI: 1.35, 2.67). After adjusting for co-morbidities and social indicators, these associations were attenuated to 1.32 (95% CI: 1.16, 1.50) and 1.64 (95% CI: 1.10, 2.46), respectively. Increased mortality was observed across all levels of cumulative use and invariant to a range of study designs and sensitivity analyses. CONCLUSIONS: Treatment initiation by metformin monotherapy in Type 2 diabetes was not associated with survival equal or superior to that of the general population without diabetes. Our contrasting findings compared with previous research are unlikely to be the result of differences in epidemiological or methodological parameters.

Early life body size, pubertal timing, and risks of benign breast disease in a large cohort of Danish female adolescents and women.

A high childhood body mass index (BMI) may be protective against benign breast disease (BBD), but little is known about the effects of other early life body size measures. Thus, we examined associations between birthweight, childhood BMI, height, and pubertal timing and BBD risks. We included 171,272 girls, born from 1930 to 1996, from the Copenhagen School Health Records Register, which contains information on birthweight, childhood anthropometry (7-13 years), age at onset of the growth spurt (OGS), and peak height velocity (PHV). During follow-up, 9361 BBD cases (15-50 years) were registered in the Danish National Patient Register. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox regressions. At all childhood ages, BMI was inversely but non-linearly associated with BBD. The association was slightly stronger in magnitude for BMI z-scores above 0 (HRage 7 = 0.86; 95%CI: 0.83-0.90 per z-score) than below 0 (HRage 7 = 0.95; 95%CI 0.91-0.99 per z-score). Associations between childhood height and BBD differed by age; at 7 years the association was an inverted U-shape, whereas at 13 years height was not associated with BBD. Ages at OGS and PHV were positively associated with BBD. Low and high birthweights were associated with lower BBD risks.   Conclusion: A high childhood BMI, a short or tall stature at young childhood ages, an early pubertal onset, and low or high birthweights are associated with reduced risks of BBD. These complex associations suggest that the role of these factors in breast tissue development during early life warrants further investigation in relation to BBD etiology. What is Known: • Benign breast disease (BBD) is common and may be an intermediary marker of breast cancer risks. • Early life body size may relate to the development of BBD, but currently little is known. What is New: • Girls with a high body mass index at school ages or with an early pubertal timing have decreased risks of BBD. • Short and tall heights at young childhood ages and low and high birthweights are associated with lower BBD risks.

Genetic contribution to the etiology of Achilles tendon rupture. A Danish nationwide register study of twins.

BACKGROUND: It is unknown if genetics contribute to the etiology of acute Achilles tendon rupture (ATR). The aims of the present study were, 1) To calculate the concordance rate for monozygotic (MZ) twins and same-sex dizygotic (SSDZ) twins and 2) to estimate the heritability of ATR. METHODS: The study was performed as a registry study using the Danish Twin Registry and the Danish National Patient Registry. RESULTS: The study sample consisted of 85,534 twins born from 1895 to 1995. Of these, 572 (0.67%) were registered with ATR in the period from 1994 to 2014. The concordance rate was 8.1% (95% CI 1.4-14.7%) for MZ twins and 4.3% (95% CI 0.7-7.9%) for SSDZ twins. The heritability of ATR was 47% (95% CI 31-62%). CONCLUSION: This study found that genetics contribute substantially to the etiology of ATR with an estimated heritability of the liability to ATR of approximately 50%. The finding generates the hypothesis that genetics play a role in the pathological changes that occur in the Achilles tendon before a rupture. The risk of ATR for a twin within a 20 year period, if the co-twin has had an ATR, was 8% for MZ twins and 4% for SSDZ twins.

Associations of maternal birth weight, childhood height, BMI, and change in height and BMI from childhood to pregnancy with risks of preterm delivery.

BACKGROUND: It remains unknown whether maternal early life body size and changes in height and BMI from childhood to pregnancy are associated with risks of having a preterm delivery. OBJECTIVES: We investigated whether a woman's birth weight, childhood height, BMI, and changes in height and BMI from childhood to pregnancy were associated with preterm delivery. METHODS: We studied 47,947 nulliparous women born from 1940 to 1996 who were included in the Copenhagen School Health Records Register with information on birth weight and childhood heights and weights at ages 7 and/or 13 years. Gestational age was obtained from the Danish Birth Register, as was prepregnancy BMI, for 13,114 women. Deliveries were classified as very (22 to <32 weeks) or moderately (32 to <37 weeks) preterm. Risk ratios (RRs) and 95% CIs were estimated using binomial regression. RESULTS: A woman's birth weight and childhood height were inversely associated with having very and moderately preterm delivery. Childhood BMI had a U-shaped association with having a very preterm delivery; at age 7 years, compared to a BMI z score of 0, the RRs were 1.31 (95% CI, 1.11-1.54) for a z score of -1 and 1.18 (95% CI, 1.01-1.38) for a z score of +1. Short stature in childhood and adulthood was associated with higher risks of very and moderately preterm delivery. Changing from a BMI at the 85th percentile at 7 years (US CDC reference) to a prepregnancy BMI of 22.5 kg/m2 was associated with RRs of 1.12 (95% CI, 0.91-1.37) and 0.88 (95% CI, 0.78-0.99) for very and moderately preterm delivery, respectively, compared to a reference woman at the 50th percentile at 7 years (22.5 kg/m2 prepregnancy BMI). CONCLUSIONS: Maternal birth weight, childhood height, and BMI are associated with very and moderately preterm delivery, although in different patterns. Consistent short stature is associated with very and moderately preterm delivery, whereas normalizing BMI from childhood to pregnancy may reduce risks of having a very preterm delivery.

Leprosy in medieval Denmark: Exploring life histories through a multi-tissue and multi-isotopic approach.

OBJECTIVES: By focusing on two Danish leprosaria (Naestved and Odense; 13th-16th c. CE) and using diet and origin as proxies, we follow a multi-isotopic approach to reconstruct life histories of patients and investigate how leprosy affected both institutionalized individuals and the medieval Danish community as a whole. MATERIALS AND METHODS: We combine archaeology, historical sources, biological anthropology, isotopic analyses (δ13 C, δ15 N, δ34 S, 87 Sr/86 Sr) and radiocarbon dating, and further analyze bones with different turnover rates (ribs and long bones). RESULTS: The δ13 C, δ15 N and δ34 S results indicate a C3 terrestrial diet with small contributions of marine protein for leprosy patients and individuals from other medieval Danish sites. A similar diet is seen through time, between males and females, and patients with and without changes on facial bones. The isotopic comparison between ribs and long bones reveals no significant dietary change. The δ34 S and 87 Sr/86 Sr results suggest that patients were local to the regions of the leprosaria. Moreover, the radiocarbon dates show a mere 50% agreement with the arm position dating method used in Denmark. CONCLUSIONS: A local origin for the leprosy patients is in line with historical evidence, unlike the small dietary contribution of marine protein. Although only 10% of the analyzed individuals have rib/long bone offsets that undoubtedly show a dietary shift, the data appear to reveal a pattern for 25 individuals (out of 50), with elevated δ13 C and/or δ15 N values in the ribs compared to the long bones, which points toward a communal type of diet and reveals organizational aspects of the institution.

Birthweight, Childhood Body Mass Index, Height and Growth, and Risk of Polycystic Ovary Syndrome.

INTRODUCTION: Adult obesity is linked with polycystic ovary syndrome (PCOS), but the importance of body size at ages before PCOS is diagnosed is unknown. OBJECTIVE: To investigate associations between a woman's own birthweight, childhood body mass index (BMI), height and growth patterns in relation to her risk of PCOS. METHODS: We included 65,665 girls from the Copenhagen School Health Records Register, born in the period 1960-1996, with information on birthweight and measured weight and height at the ages of 7-13 years. Overweight was defined using International Obesity Task Force (IOTF) criteria. From the Danish National Patient Register, 606 women aged 15-50 years were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox regression analysis. RESULTS: Birthweight was not associated with PCOS. At the age of 7-13 years, girls with overweight had a higher risk of developing PCOS than girls without overweight; HR 2.83 (95% CI 2.34-3.42) at age 7 years and 2.99 (95% CI 2.38-3.76) at age 13 years. Furthermore, girls with overweight at both 7 and 13 years had a higher risk of developing PCOS than girls without overweight or overweight at only one age. Height was positively associated with PCOS risk at all ages. Girls who were persistently tall or changed from tall to average height had a higher risk of developing PCOS than girls with average height growth. CONCLUSION: Overweight and tall stature in childhood are positively associated with PCOS risk, but birthweight is not.

Risk of gestational diabetes mellitus in nulliparous women - Associations with early life body size and change in body mass index from childhood to adulthood.

AIMS: We examined whether a woman's birthweight, childhood height, body mass index (BMI), and BMI changes from childhood to pregnancy were associated with risks of gestational diabetes mellitus (GDM). METHODS: We studied 13,031 women from the Copenhagen School Health Records Register born 1959-1996 with birthweight and measured anthropometric information at ages 7 and/or 13. The diagnosis of GDM (n = 255) was obtained from a national health register. Risk ratios (RR) were estimated using log-linear binomial regression. RESULTS: Own birthweight and childhood height were inversely associated with GDM. Girls with overweight at age 7 had a higher risk of GDM than girls with normal-weight (RR: 1.79, 95% CI: 1.31, 2.47). Compared to women with normal-weight in childhood and adulthood, risks of GDM were higher in women who developed overweight from age 7 to pregnancy (RR: 4.62; 3.48, 6.14) or had overweight at both times (RR: 4.71; 3.24, 6.85). In women whose BMI normalized from age 7 to pregnancy the RR for GDM was 1.08 (0.47, 2.46). CONCLUSIONS: Lower birthweight, shorter childhood height, and higher childhood BMI are associated with increased risks of GDM. Efforts to help girls maintain a normal BMI before pregnancy may be warranted to minimize risks of GDM.

Associations of childhood BMI and change in BMI from childhood to adulthood with risks of hypertensive disorders in pregnancy.

BACKGROUND: Maternal overweight (including obesity) is an established risk factor for gestational hypertension and pre-eclampsia. However, it is largely unknown whether body size before adulthood relates to these diseases. OBJECTIVES: We examined whether childhood BMI (in kg/m2) and changes in BMI from childhood to adulthood were associated with gestational hypertension and pre-eclampsia. METHODS: Using the Copenhagen School Health Records Register, we studied 49,600 women born between 1940 and 1996 with height and weight measurements at 7 y and/or 13 y who had their first singleton birth between ages 18 and 45 y. Women with gestational hypertension (n = 496) and pre-eclampsia (n = 1804) were identified from the International Classification of Disease codes in the Danish National Patient Register. Adult overweight (including obesity) was defined as a BMI ≥25. We used log-linear binomial regression to estimate risk ratios (RRs) and 95% CIs. RESULTS: At 13 y, as BMI increased above average (z score >0, or the 42nd percentile of the CDC BMI reference), RR for gestational hypertension was 1.66 (95% CI: 1.42, 1.94) and that for pre-eclampsia was 1.57 (95% CI: 1.46, 1.70) per BMI z score. In a subset of 13,160 women, development of overweight from childhood to adulthood and having overweight at both ages were associated with higher risks of the outcomes than in those with a normal BMI at both ages. No increased risks were observed in women whose BMI normalized from childhood to adulthood: RR was 2.04 (95% CI: 0.93, 4.47) for gestational hypertension and 1.11 (95% CI: 0.63, 1.93) for pre-eclampsia. CONCLUSIONS: Above-average childhood BMI values and development of overweight from childhood to adulthood were associated with increased risks of gestational hypertension and pre-eclampsia, whereas normalizing BMI from childhood to conception attenuated the risks. Thus, interventions aiming at normalizing BMI in girls with high values may be warranted to help prevent these obstetric diseases.

Birthweight, childhood overweight, height and growth and adult cancer risks: a review of studies using the Copenhagen School Health Records Register.

BACKGROUND: Most identified risk factors for cancer primarily occur in adulthood. As cancers generally have long latency periods, it is possible that risk factors acting earlier in life and accumulation of risks across the life course are important. Thus, focusing only on adult overweight as a modifiable risk factor may overlook childhood as an important aetiologic time window when body size is relevant for future cancer risks. The objective of this study was to review the evidence for associations between birthweight, body mass index (BMI), height and growth from 7-13 years and adult cancer risks based on studies using the Copenhagen School Health Records Register. METHODS: The register contains measured anthropometric information on 372,636 children born in 1930-1989. All studies examining associations between early life body size and risks of adult cancer (until 85 years, diagnosed in 1968-2015) were included, comprising 31 studies on 16 different cancer sites. Cancer diagnoses were retrieved via individual-level linkages to the Danish Cancer Registry. RESULTS: Birthweight was differentially associated with bladder, breast, colon, glioma, Hodgkin's disease, liver, kidney (renal cell), melanoma, ovarian, rectal, testicular and thyroid cancer. BMI in childhood was positively associated with risks of bladder (only late childhood), colon, endometrial, kidney, liver, oesophageal (only late childhood), ovarian, pancreatic (<70 years), prostate (only before childhood height adjustment) and thyroid cancer, whereas it was inversely associated with breast cancer. Child height was positively associated with breast, colon, endometrial, glioma, Hodgkin's disease, kidney, melanoma, oesophageal (only women), ovarian, prostate, testicular and thyroid cancer and inversely associated with bladder cancer. Greater than average increases in childhood BMI or linear growth at ages 7-13 increased risks of several cancers. CONCLUSIONS: Early life body size and growth are associated with many, but not all adult cancers, suggesting that the aetiology of several cancers may lie earlier in life than previously thought.

A millennium of population change in pre-modern Danish Ribe.

Denmark experienced major socioeconomic changes, including overall population growth, during the Viking, medieval and post-medieval periods from ca. AD 800 to 1800. Archaeological skeletons provide a unique perspective on the population structure of Ribe, a Danish town in Jutland, during the millennium that immediately precedes the industrialization of northern Europe. This skeletal study adds temporal depth to our understanding of an overall trend toward longer life as seen from historical records and in modern studies. Adult male and female mean age at death and mortality profiles during three time periods are based on 943 adult skeletons from three urban cemeteries that collectively represent a cross-section of this urban community. For both males and females, the mean age at death decreased slightly from the Viking (males 38.5 years, females 38.6 years) to the medieval (males 37.4 years, females 36.9 years) periods. This decline was followed by an increase in mean age at death for both sexes from the medieval to post-medieval (males 40.4 years, females 43.2 years) periods, a notable gain of 3.0 and 6.3 years for men and women, respectively.

Clonal hematopoiesis in elderly twins: concordance, discordance, and mortality.

Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is defined by mutations in myeloid cancer-associated genes with a variant allele frequency of at least 2%. Recent studies have suggested a possible genetic predisposition to CH. To further explore this phenomenon, we conducted a population-based study of 594 twins from 299 pairs aged 73 to 94 years, all with >20 years' follow-up. We sequenced DNA from peripheral blood with a customized 21-gene panel at a median coverage of 6179X. The casewise concordance rates for mutations were calculated to assess genetic predisposition. Mutations were identified in 214 (36%) of the twins. Whereas 20 twin pairs had mutations within the same genes, the exact same mutation was only observed in 2 twin pairs. No significant difference in casewise concordance between monozygotic and dizygotic twins was found for any specific gene, subgroup, or CHIP mutations overall, and no significant heritability could be detected. In pairs discordant for CHIP mutations, we tested if the affected twin died before the unaffected twin, as a direct measurement of the association of having CH when controlling for familial factors. A total of 127 twin pairs were discordant for carrying a mutation, and in 61 (48%) cases, the affected twin died first (P = .72). Overall, we did not find a genetic predisposition to CHIP mutations in this twin study. The previously described negative association of CHIP mutations on survival could not be confirmed in a direct comparison among twin pairs that were discordant for CHIP mutations.

Changes and correlations in height from 7 to 69 years of age across the birth years of 1930 to 1989.

OBJECTIVES: The aims of this study were to describe changes in height during childhood and to investigate potential changes in the proportion of children attaining final height in childhood and in correlations between child and adult height across birth cohorts. METHODS: We included 363 059 children (179 906 girls) from the Copenhagen School Health Records Register, who were born between 1930 and 1989, with height measurements at ages 7, 10, or 13 years. Linkages to data resources containing adult height values between ages 18 and 69 years were possible for a subpopulation of 96 133 individuals (23 051 women). Birth years were categorized as 1930 to 1939, 1940 to 1949, and 1950 to 1989. Descriptive height statistics were estimated by birth years and birth cohorts. Height correlations were examined using sex- and age-specific partial Pearson correlation analyses and meta-regression techniques. RESULTS: Across 60 birth years, mean child heights at age 7 increased by 2.9 cm in girls and 3.0 cm in boys, and adult heights increased as well. The proportions of children attaining final height by age 13 remained low across the birth cohorts; nonetheless, there was a significant increase from 0.7% to 1.5% in girls only (P < .0001). Both child-child and child-adult height correlations were strong and remained relatively stable across birth cohorts. CONCLUSIONS: Mean child and adult height increased during the study period, but the proportion of children attaining final height at age 13 remained low. Child-child and child-adult height correlations were largely unchanged across birth cohorts.

The Danish Twin Registry: An Updated Overview.

The Danish Twin Registry (DTR) was established in the 1950s, when twins born from 1870 to 1910 were ascertained, and has since been extended to include twins from birth cohorts until 2009. The DTR currently comprises of more than 175,000 twins from the 140 birth cohorts. This makes the DTR the oldest nationwide twin register and among the largest in the world. The combination of data from several surveys, including biological samples and repeated measurements on the same individuals, and data from Danish national registers provides a unique resource for a wide range of twin studies. This article provides an updated overview of the data in the DTR: First, we provide a summary of the establishment of the register, the different ascertainment methods and the twins included; then follows an overview of major surveys conducted in the DTR since 1994 and a description of the DTR biobank, including a description of the molecular data created so far; finally, a short description is given of the linkage to Danish national registers at Statistics Denmark and some recent examples of studies using the various data resources in the DTR are highlighted.