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1.  Childhood height and body mass index were associated with risk of adult thyroid cancer in a large cohort study 
Cancer research  2013;74(1):235-242.
Taller stature and obesity in adulthood have been consistently associated with an increased risk of thyroid cancer, but few studies have investigated the role of childhood body size. Using data from a large prospective cohort, we examined associations for height and body mass index (BMI) at ages 7–13 with risk of thyroid cancer in later life. The study population included 321,085 children from the Copenhagen School Health Records Register, born between 1930 and 1989 in Copenhagen, Denmark, with measurements of height and weight from 7–13 years of age. These data were linked with the Danish Cancer Registry to identify incident thyroid cancer cases (1968–2010). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for age-and sex-specific height and BMI standard deviation scores (SDSs) using proportional hazards models stratified by birth cohort and sex. During follow-up (median=38.6 years), 171 women and 64 men were diagnosed with thyroid cancer. Both height and BMI were positively associated with thyroid cancer risk, and these associations were similar by age at measurement. Using age 10 as an example, HRs per 1-unit increase in SDS for height (approximately 6–7 cm) and BMI (approximately 1.5–2 kg/m2) were 1.22 (95% CI: 1.07–1.40) and 1.15 (95% CI: 1.00–1.34), respectively. These results, together with the relatively young ages at which thyroid cancers are diagnosed compared with other malignancies, suggest a potential link between early-life factors related to growth and body weight and thyroid carcinogenesis.
PMCID: PMC3891884  PMID: 24247722
prospective study; obesity; body mass index; height; childhood; adolescence; thyroid neoplasms
2.  Childhood height and birth weight in relation to future prostate cancer risk: a cohort study based on the Copenhagen School Health Records Register 
Adult height has been positively associated with prostate cancer risk. However, the exposure window of importance is currently unknown and assessments of height during earlier growth periods are scarce. In addition, the association between birth weight and prostate cancer remains undetermined. We assessed these relationships a cohort of the Copenhagen School Health Records Register (CSHRR).
The CSHRR comprises 372,636 school children. For boys born between the 1930’s and 1969, birth weight and annual childhood heights—measured between ages 7 and 13 years—were analyzed in relation to prostate cancer risk. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95 percent confidence intervals (95%CI).
There were 125,211 males for analysis, 2,987 of who were subsequently diagnosed with prostate cancer during 2.57 million person-years of follow-up. Height z-score was significantly associated with prostate cancer risk at all ages (HR~1.13). Height at age 13 years was more important than height change (p=0.024) and height at age 7 years (p=0.024), when estimates from mutually adjusted models were compared. Adjustment of birth weight did not alter estimates ascertained. Birth weight was not associated with prostate cancer risk.
The association between childhood height and prostate cancer risk was driven by height at age 13 years.
Our findings implicate late childhood, adolescence and adulthood growth periods as containing the exposure window(s) of interest that underlies the association between height and prostate cancer. The causal factor may not be singular given the complexity of both human growth and carcinogenesis.
PMCID: PMC3863763  PMID: 24089459
prostate neoplasms; body height; growth; body weights and measures; birth weight; cohort studies
4.  Atypical Ductal Hyperplasia at the Margin of Lumpectomy Performed for Early Stage Breast Cancer: Is there Enough Evidence to Formulate Guidelines? 
Background. Negative margins are associated with a reduced risk of ipsilateral breast tumor recurrence (IBTR) in women with early stage breast cancer treated with breast conserving surgery (BCS). Not infrequently, atypical ductal hyperplasia (ADH) is reported as involving the margin of a BCS specimen, and there is no consensus among surgeons or pathologists on how to approach this diagnosis resulting in varied reexcision practices among breast surgeons. The purpose of this paper is to establish a reasonable approach to guide the treatment of ADH involving the margin after BCS for early stage breast cancer. Methods. the published literature was reviewed using the PubMed site from the US National Library of Medicine. Conclusions. ADH at the margin of a BCS specimen performed for early stage breast cancer is a controversial pathological diagnosis subject to large interobserver variability. There is not enough data evaluating this diagnosis to change current practice patterns; however, it is reasonable to consider reexcision for ADH involving a surgical margin, especially if it coexists with low grade DCIS. Further studies with longer followup and closer attention to ADH at the margin are needed to formulate treatment guidelines.
PMCID: PMC3529487  PMID: 23304477
5.  Trends in Parent-Child Correlations of Childhood Body Mass Index during the Development of the Obesity Epidemic 
PLoS ONE  2014;9(10):e109932.
The intergenerational resemblance in body mass index may have increased during the development of the obesity epidemic due to changes in environment and/or expression of genetic predisposition.
This study investigates trends in intergenerational correlations of childhood body mass index (BMI; kg/m2) during the emergence of the obesity epidemic.
The study population was derived from the Copenhagen School Health Records Register, which includes height and weight measurements since birth year 1930. Mothers and fathers with BMIs available at ages 7 (n = 25,923 and n = 20,972) or 13 years (n = 26,750 and n = 21,397), respectively, were linked through the civil registration system introduced in 1968 to their children with BMIs available at age 7 years. Age- and sex-specific BMI z-scores were calculated. Correlations were estimated across eight intervals of child birth years (1952–1989) separately by sex. Trends in these correlations were examined. Whereas the mother-child correlations reflected the biological relationship, a likely decline in the assignment of non-biological fathers through the registration system across time must be considered when interpreting the father-child correlations.
The BMI correlations between mothers and sons ranged from 0.29–0.36 and they decreased marginally, albeit significantly across time at ages 7–7 years (−0.002/year, p = 0.006), whereas those at 13–7 years remained stable (<0.0004/year, p = 0.96). Mother-daughter correlations ranged from 0.30–0.34, and they were stable at ages 7–7 years (0.0001/year, p = 0.84) and at 13–7 years (0.0004/year, p = 0.56). In contrast, father-son correlations increased significantly during this period, both at ages 7–7 (0.002/year, p = 0.007) and at ages 13–7 years (0.003/year, p<0.001), whereas the increase in father-daughter correlations were insignificant both at ages 7–7 (0.001/year, p = 0.37) and at ages 13–7 years (0.001/year, p = 0.18).
During the obesity epidemics development, the intergenerational resemblance with mothers remained stable, whereas the father-child BMI resemblance increased, possibly reflecting changes in family relationships, and unlikely to have influenced the epidemic.
PMCID: PMC4201474  PMID: 25329656
6.  Comparison of [99mTc]Tilmanocept and Filtered [99mTc]Sulfur Colloid for Identification of SLNs in Breast Cancer Patients 
The efficacy of sentinel lymph node (SLN) surgery requires targeted removal of first-draining nodes; however, frequently more nodes are removed than necessary. [99mTc]tilmanocept (TcTM) is a molecular-targeted radiopharmaceutical specifically designed for SLN mapping. We evaluated technical outcomes of SLN biopsy in breast cancer patients mapped with TcTM + vital blue dye (VBD) versus filtered [99mTc]sulfur colloid (fTcSC) + VBD.
There were 84 versus 115 patients in the TcTM versus fTcSC cohorts, respectively. Main measures were the number of SLNs removed per patient and factors influencing number of nodes removed. We also evaluated whether the radiotracer injected affected the proportion of positive nodes removed in node-positive patients.
Fewer nodes were removed among patients mapped with TcTM compared to fTcSC (mean TcTM: 1.85 vs. fTcSC: 3.24, p < 0.001). Logistic regression analysis adjusted for tumor characteristics showed that injection of fTcSC (p < 0.001) independently predicted removal of greater than 3 nodes. A similar proportion of patients was identified as node-positive, whether mapped with TcTM or with fTcSC (TcTM: 24 % vs. fTcSC: 17 %, p = 0.3); however, TcTM detected a greater proportion of positive nodes among node-positive patients compared with fTcSC (0.73 vs. 0.43, p = 0.001).
Patients undergoing SLN biopsy with TcTM required fewer SLNs to identify the same rate of node-positive patients compared with fTcSC in breast cancer patients with similar risk of axillary metastatic disease. These data suggest that a molecularly targeted mechanism of SLN identification may reduce the total number of nodes necessary for accurate axillary staging.
PMCID: PMC4273083  PMID: 25069859
7.  Birth weight, childhood body mass index, and height in relation to mammographic density and breast cancer: a register-based cohort study 
High breast density, a strong predictor of breast cancer may be determined early in life. Childhood anthropometric factors have been related to breast cancer and breast density, but rarely simultaneously. We examined whether mammographic density (MD) mediates an association of birth weight, childhood body mass index (BMI), and height with the risk of breast cancer.
13,572 women (50 to 69 years) in the Copenhagen mammography screening program (1991 through 2001) with childhood anthropometric measurements in the Copenhagen School Health Records Register were followed for breast cancer until 2010. With logistic and Cox regression models, we investigated associations among birth weight, height, and BMI at ages 7 to 13 years with MD (mixed/dense or fatty) and breast cancer, respectively.
8,194 (60.4%) women had mixed/dense breasts, and 716 (5.3%) developed breast cancer. Childhood BMI was significantly inversely related to having mixed/dense breasts at all ages, with odds ratios (95% confidence intervals) ranging from 0.69 (0.66 to 0.72) at age 7 to 0.56 (0.53 to 0.58) at age 13, per one-unit increase in z-score. No statistically significant associations were detected between birth weight and MD, height and MD, or birth weight and breast cancer risk. BMI was inversely associated with breast cancer, with hazard ratios of 0.91 (0.83 to 0.99) at age 7 and 0.92 (0.84 to 1.00) at age 13, whereas height was positively associated with breast cancer risk (age 7, 1.06 (0.98 to 1.14) and age 13, 1.08 (1.00 to 1.16)). After additional adjustment for MD, associations of BMI with breast cancer diminished (age 7, 0.97 (0.88 to 1.06) and age 13, 1.01 (0.93 to 1.11)), but remained with height (age 7, 1.06 (0.99 to 1.15) and age 13, 1.09 (1.01 to 1.17)).
Among women 50 years and older, childhood body fatness was inversely associated with the breast cancer risk, possibly via a mechanism mediated by MD, at least partially. Childhood tallness was positively associated with breast cancer risk, seemingly via a pathway independent of MD. Birth weight was not associated with MD or breast cancer in this age group.
PMCID: PMC3978910  PMID: 24443815
8.  Contributions of Incidence and Persistence to the Prevalence of Childhood Obesity during the Emerging Epidemic in Denmark 
PLoS ONE  2012;7(8):e42521.
Prevalence of obesity is the result of preceding incidence of newly developed obesity and persistence of obesity. We investigated whether increasing incidence and/or persistence during childhood drove the prevalence of childhood obesity during the emerging epidemic.
Height and weight were measured at ages 7 and 13 years in 192,992 Danish school children born 1930–1969. Trends in the incidence (proportion obese at 13 years among those not obese at 7 years) and persistence (proportion obese at 13 years among those obese at 7 years) across birth cohort periods (1930–41 with low stable prevalence of obesity, 1942–51 with increasing prevalence, 1952–69 with the higher, but stable prevalence) were investigated. Logistic regression was used to examine the associations between BMI at 7 years as a continuous trait, allowing interactions with the birth cohorts, and occurrence of obesity at 13 years.
The prevalence of obesity was similar at 7 and 13 years and increased across birth cohorts in boys from around 0.1% to 0.5% and in girls from around 0.3% to 0.7%. The incidence of obesity between ages 7 and 13 years increased from 0.15% to 0.35% in boys and from 0.20% to 0.44% in girls. The persistence increased from 28.6% to 41.4% in boys and from 16.4% to 31.0% in girls. Despite a decrease over time, the remission of obesity occurred in >60% of obese children in the last birth cohort. However, the odds ratios of obesity at age 13 years in relation to the full range of BMI at 7 years remained unchanged across the birth cohort periods.
The development of the obesity epidemic in children was due to an increase in both incidence and persistence of obesity. Contrary to prevailing expectations, a large, although declining, proportion of children obese at an early age underwent remission during childhood.
PMCID: PMC3416857  PMID: 22900026
9.  Assortative marriages by body mass index have increased simultaneously with the obesity epidemic 
Frontiers in Genetics  2012;3:125.
Background: The genetic predisposition to obesity may have contributed to the obesity epidemic through assortative mating. We investigated whether spouses were positively assorted by body mass index (BMI; = kg/m2) in late childhood, and whether changes in assorted marriage by upper BMI-percentiles occurred during the obesity epidemic. Methods: In the Copenhagen School Health Records Register (CSHRR) boys and girls with measures of BMI at age 13 years later became 37,792 spousal-pairs who married between 1945 and 2010. Trends in the spousal BMI correlations using sex-, age-, and birth cohort-specific BMI z-scores across time were investigated. Odds ratios (ORs) of marriage among spouses both with BMI z-scores >90th or >95th percentile compared with marriage among spouses ≤90th percentile were analyzed for marriages entered during the years prior to (1945–1970), and during the obesity epidemic (1971–2010). Findings: Spousal BMI correlations were around 0.05 and stayed similar across time. ORs of marriage among spouses with BMIs >90th percentile at age 13 were 1.21, 1.05–1.39, in 1945–1970, and increased to 1.63, 1.40–1.91, in 1971–2010 (p = 0.006). ORs of marriage among spouses both >95th BMI percentile were higher and increased more; from 1.39, 1.10–1.81, to 2.39, 1.85–3.09 (p = 0.004). Interpretation: Spousal correlations by pre-marital BMIs were small and stable during the past 65 years. Yet, there were assorted marriages between spouses with high BMI at age 13 years and the tendency increased alongside with the obesity epidemic which may increase the offsprings' predisposition to obesity.
PMCID: PMC3458436  PMID: 23056005
assortative mating; body mass index; childhood; obesity; overweight; phenotype; human genetics
10.  Growth in Height in Childhood and Risk of Coronary Heart Disease in Adult Men and Women 
PLoS ONE  2012;7(1):e30476.
Adult height is inversely associated with the risk of coronary heart disease (CHD), but it is still unknown which phase of the human growth period is critical for the formation of this association. We investigated the association between growth in height from 7 to 13 years of age and the risk of CHD in adulthood.
Methods and Findings
The heights of almost all children born 1930 through 1976 who attended school in the Copenhagen municipality (232,063 children) were measured annually from 7 to 13 years of age. Birth weight data were available since 1936. Fatal and non-fatal CHD events were ascertained by register linkage until 2008 (25,214 cases). Hazard ratios (HR) with 95% confidence intervals (CI) were estimated by Cox proportional hazards regression for height z-scores (standard deviation units) and change in height z-scores. Height z-scores were inversely related to the risk of CHD. The association was strongest at 7 years of age (HR = 0.91, CI 0.90–0.92 in boys and 0.88, CI 0.86–0.90 in girls) and steadily weakened thereafter, yet it still remained at 13 years of age (HR = 0.95, CI 0.94–0.97 and 0.91, CI 0.89–0.93, boys and girls respectively). The associations were not modified by birth weight. Independent of the age-specific risk, rapid growth was associated with an increased CHD risk, most pronounced between 9 and 11 years in girls (HR = 1.22, CI 1.14–1.31) and between 11 and 13 years in boys (HR = 1.28, CI 1.22–1.33) per unit increase in z-score. Adjustment for body mass index somewhat strengthened the associations of CHD risk with height and weakened the association with growth.
Risk of CHD in adulthood is inversely related to height at ages 7 through 13 years, but strongest in the youngest, and, independently hereof, the risk increased by growth velocity.
PMCID: PMC3265486  PMID: 22291964
11.  Childhood Body-Mass Index and the Risk of Coronary Heart Disease in Adulthood 
The New England journal of medicine  2007;357(23):2329-2337.
The worldwide epidemic of childhood obesity is progressing at an alarming rate. Risk factors for coronary heart disease (CHD) are already identifiable in overweight children. The severity of the long-term effects of excess childhood weight on CHD, however, remains unknown.
We investigated the association between body-mass index (BMI) in childhood (7 through 13 years of age) and CHD in adulthood (25 years of age or older), with and without adjustment for birth weight. The subjects were a cohort of 276,835 Danish schoolchildren for whom measurements of height and weight were available. CHD events were ascertained by linkage to national registers. Cox regression analyses were performed.
In 5,063,622 person-years of follow-up, 10,235 men and 4318 women for whom childhood BMI data were available received a diagnosis of CHD or died of CHD as adults. The risk of any CHD event, a nonfatal event, and a fatal event among adults was positively associated with BMI at 7 to 13 years of age for boys and 10 to 13 years of age for girls. The associations were linear for each age, and the risk increased across the entire BMI distribution. Furthermore, the risk increased as the age of the child increased. Adjustment for birth weight strengthened the results.
Higher BMI during childhood is associated with an increased risk of CHD in adulthood. The associations are stronger in boys than in girls and increase with the age of the child in both sexes. Our findings suggest that as children are becoming heavier worldwide, greater numbers of them are at risk of having CHD in adulthood.
PMCID: PMC3062903  PMID: 18057335
12.  Birth Weight, Childhood Body Mass Index and Risk of Coronary Heart Disease in Adults: Combined Historical Cohort Studies 
PLoS ONE  2010;5(11):e14126.
Low birth weight and high childhood body mass index (BMI) is each associated with an increased risk of coronary heart disease (CHD) in adult life. We studied individual and combined associations of birth weight and childhood BMI with the risk of CHD in adulthood.
Methods/Principal Findings
Birth weight and BMI at age seven years were available in 216,771 Danish and Finnish individuals born 1924–1976. Linkage to national registers for hospitalization and causes of death identified 8,805 CHD events during up to 33 years of follow-up (median = 24 years) after age 25 years. Analyses were conducted with Cox regression based on restricted cubic splines. Using median birth weight of 3.4 kg as reference, a non-linear relation between birth weight and CHD was found. It was not significantly different between cohorts, or between men and women, nor was the association altered by childhood BMI. For birth weights below 3.4 kg, the risk of CHD increased linearly and reached 1.28 (95% confidence limits: 1.13 to 1.44) at 2 kg. Above 3.4 kg the association weakened, and from about 4 kg there was virtually no association. BMI at age seven years was strongly positively associated with the risk of CHD and the relation was not altered by birth weight. The excess risk in individuals with a birth weight of 2.5 kg and a BMI of 17.7 kg/m2 at age seven years was 44% (95% CI: 30% to 59%) compared with individuals with median values of birth weight (3.4 kg) and BMI (15.3 kg/m2).
Birth weight and BMI at age seven years appeared independently associated with the risk of CHD in adulthood. From a public health perspective we suggest that particular attention should be paid to children with a birth weight below the average in combination with excess relative weight in childhood.
PMCID: PMC2993956  PMID: 21124730
13.  Prenatal Stress Exposure Related to Maternal Bereavement and Risk of Childhood Overweight 
PLoS ONE  2010;5(7):e11896.
It has been suggested that prenatal stress contributes to the risk of obesity later in life. In a population–based cohort study, we examined whether prenatal stress related to maternal bereavement during pregnancy was associated with the risk of overweight in offspring during school age.
Methodology/Principal Findings
We followed 65,212 children born in Denmark from 1970–1989 who underwent health examinations from 7 to 13 years of age in public or private schools in Copenhagen. We identified 459 children as exposed to prenatal stress, defined by being born to mothers who were bereaved by death of a close family member from one year before pregnancy until birth of the child. We compared the prevalence of overweight between the exposed and the unexposed. Body mass index (BMI) values and prevalence of overweight were higher in the exposed children, but not significantly so until from 10 years of age and onwards, as compared with the unexposed children. For example, the adjusted odds ratio (OR) for overweight was 1.68 (95% confidence interval [CI] 1.08–2.61) at 12 years of age and 1.63 (95% CI 1.00–2.61) at 13 years of age. The highest ORs were observed when the death occurred in the period from 6 to 0 month before pregnancy (OR 3.31, 95% CI 1.71–6.42 at age 12, and OR 2.31, 95% CI 1.08–4.97 at age 13).
Our results suggest that severe pre-pregnancy stress is associated with an increased risk of overweight in the offspring in later childhood.
PMCID: PMC2912844  PMID: 20689593
14.  Correcting for Fat Mass Improves DXA Quantification of Quadriceps Specific Strength in Obese Adults Aged 50–59 Years 
Dual-energy X-ray absorptiometry (DXA) is widely used for bone mineral density and body composition assessments. However, DXA is known to overestimate muscle mass in obese adults. We used single-slice CT (ssCT) to derive a correction factor to enhance accuracy of DXA estimation of specific strength (strength per unit muscle). One hundred and sixty-two adults (age: 55.0 ± 2.7 yr, range: 50–59) were enrolled in this cross-sectional study and divided into groups based on body mass index (BMI: < 30, 30–35, and ≥35). BMI groups did not differ in age, knee extensor strength (KES), thigh lean mass by DXA, or quadriceps cross-sectional area (CSA) by ssCT. Specific strength (KES/CSA) correlated with an uncorrected estimate of DXA–specific strength (r = 0.82, 0.53, 0.84 and 0.74, 0.59, 0.57, p < 0.001) in the lowest to highest BMI groups in men and women, respectively. Stronger correlations were achieved through correcting for BMI, age, and sex in estimating DXA—specific strength (r = 0.81, 0.79, and 0.96 in the lowest to highest BMI groups in men and 0.94, 0.81, 0.85 in women, p < 0.0001). Quantification of knee extensor—specific strength by DXA in men with BMI >30 and all BMI groups in women greatly improved using a correction factor for DXA estimates of thigh lean mass.
PMCID: PMC2906608  PMID: 19121597
CT; dual-energy X-ray absorptiometry; fat-free mass; knee extensor strength; obesity; specific strength
16.  Life Course Path Analysis of Birth Weight, Childhood Growth, and Adult Systolic Blood Pressure 
American Journal of Epidemiology  2009;169(10):1167-1178.
The inverse associations between birth weight and later adverse health outcomes and the positive associations between adult body size and poor health imply that increases in relative body size between birth and adulthood may be undesirable. In this paper, the authors describe life course path analysis, a method that can be used to jointly estimate associations between body sizes at different time points and associations of body sizes throughout life with health outcomes. Additionally, this method makes it possible to assess both the direct effect and the indirect effect mediated through later body size, and thereby the total effect, of size and changes in size on later outcomes. Using data on childhood body size and adult systolic blood pressure from a sample of 1,284 Danish men born between 1936 and 1970, the authors compared results from path analysis with results from 3 standard regression methods. Path analysis produced easily interpretable results, and compared with standard regression methods it produced a noteworthy gain in statistical power. The effect of change in relative body size on adult blood pressure was more pronounced after age 11 years than in earlier childhood. These results suggest that increases in body size prior to age 11 years are less harmful to adult blood pressure than increases occurring after this age.
PMCID: PMC2732973  PMID: 19357327
birth weight; blood pressure; body mass index; child; epidemiologic methods; growth
17.  Birth Weight in Relation to Leisure Time Physical Activity in Adolescence and Adulthood: Meta-Analysis of Results from 13 Nordic Cohorts 
PLoS ONE  2009;4(12):e8192.
Prenatal life exposures, potentially manifested as altered birth size, may influence the later risk of major chronic diseases through direct biologic effects on disease processes, but also by modifying adult behaviors such as physical activity that may influence later disease risk.
Methods/Principal Findings
We investigated the association between birth weight and leisure time physical activity (LTPA) in 43,482 adolescents and adults from 13 Nordic cohorts. Random effects meta-analyses were performed on categorical estimates from cohort-, age-, sex- and birth weight specific analyses. Birth weight showed a reverse U-shaped association with later LTPA; within the range of normal weight the association was negligible but weights below and above this range were associated with a lower probability of undertaking LTPA. Compared with the reference category (3.26–3.75 kg), the birth weight categories of 1.26–1.75, 1.76–2.25, 2.26–2.75, and 4.76–5.25 kg, had odds ratios of 0.67 (95% confidence interval: 0.47, 0.94), 0.72 (0.59, 0.88), 0.89 (0.79, 0.99), and 0.65 (0.50, 0.86), respectively. The shape and strength of the birth weight-LTPA association was virtually independent of sex, age, gestational age, educational level, concurrent body mass index, and smoking.
The association between birth weight and undertaking LTPA is very weak within the normal birth weight range, but both low and high birth weights are associated with a lower probability of undertaking LTPA, which hence may be a mediator between prenatal influences and later disease risk.
PMCID: PMC2790716  PMID: 20016780

Results 1-17 (17)