Ellen Aagaard Nohr

Does Low Participation in Cohort Studies Induce Bias

Background: Participation rates in large cohort studies have decreased during the last 2 decades. The consequences of this trend for relative risk estimation are unknown. Methods: The impact of a low participation rate (30%) on the Danish National Birth Cohort was examined among 49,751 women from the source population, including 15,373 participants in the cohort study. On the basis of independent data collection, we estimated odds ratios (ORs) in the source population and among participants for 3 exposure-risk associations: (a) in vitro fertilization and preterm birth, (b) smoking during pregnancy and birth of a small-for-gestational-age infant, and (c) prepregnancy body mass index and antepartum stillbirth. The effect of nonparticipation was described by a relative odds ratio (ROR), calculated as the OR(participants)/OR(source population). Two methods for calculation of confidence intervals for the relative odds ratio also were assessed. Results: The effect of nonparticipation on the selected ORs was small. The relative ORs were close to one and the bias was never larger than 16%, although some of the confidence intervals were wide. The 2 methods for calculation of confidence intervals gave very similar results and a small simulation study showed that the coverage probabilities were close to the 95% nominal level. Conclusion: For the 3 chosen associations, the ORs were not biased by nonparticipation. The results are reassuring for studies based on the Danish cohort and similar cohorts of pregnant women. The methodology used to compute confidence intervals for the relative odds ratios performed well in the scenarios considered.

Prepregnancy obesity and fetal death: a study within the Danish National Birth Cohort.

Objective: To examine the association between high prepregnancy body mass index and fetal death, allowing for the effects of gestational age, weight gain, and maternal diseases in pregnancy. Methods: Prepregnancy body mass index (BMI) and fetal death were examined in the Danish National Birth Cohort among 54,505 pregnant women who participated in a comprehensive interview during the second trimester. Pregnancy outcomes were obtained from registers and medical records. Cox regression analyses with delayed entry and time-dependent covariates were used to estimate the risk of fetal death. Results: Compared with normal-weight women (18.5 ≤ BMI < 25), the risks of fetal death among obese women (BMI ≥ 30), expressed as adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were as follows: before week 14: 0.8 (0.5–1.4), weeks 14–19: 1.6 (1.0–2.5), weeks 20–27: 1.9 (1.1–3.3), weeks 28–36: 2.1 (1.0–4.4), weeks 37–39: 3.5 (1.9–6.4), and weeks 40+: 4.6 (1.6–13.4). Overweight women (25 ≤ BMI < 30) also experienced a higher risk after 28 weeks, and especially after 40 weeks of gestation (HR 2.9, 95% CI 1.1–7.7). Analysis of stillbirth (fetal death at 28+ completed weeks of gestation) indicated that the effects were not due to obesity-related diseases in pregnancy, nor was weight gain associated with stillbirth. The increased risk of stillbirth among overweight and obese women was partly attributable to inadequate placental function (crude odds ratios 2.1, 95% CI 1.0–4.4, and 5.2, 95% CI 2.5–10.9, respectively). Conclusion: Prepregnancy obesity was associated with an increasing excess risk of fetal death with advancing gestation, and placental dysfunction may be a possible contributing factor. Level of Evidence: II-2

Complications after cardiac implantable electronic device implantations: an analysis of a complete, nationwide cohort in Denmark

Aims Complications after cardiac implantable electronic device (CIED) treatment, including permanent pacemakers (PMs), cardiac resynchronization therapy devices with defibrillators (CRT-Ds) or without (CRT-Ps), and implantable cardioverter defibrillators (ICDs), are associated with increased patient morbidity, healthcare costs, and possibly increased mortality. Methods and results Population-based cohort study in all Danish patients who underwent a CIED procedure from May 2010 to April 2011. Data on complications were gathered on review of all patient charts while baseline data were obtained from the Danish Pacemaker and ICD Register. Adjusted risk ratios (aRRs) with 95% confidence intervals were estimated using binary regression. The study population consisted of 5918 consecutive patients. A total of 562 patients (9.5%) experienced at least one complication. The risk of any complication was higher if the patient was a female (aRR 1.3; 1.1–1.6), underweight (aRR 1.5; 1.1–2.3), implanted in a centre with an annual volume <750 procedures (0–249 procedures: aRR 1.6; 1.1–2.2, 250–499: aRR 2.0; 1.6–2.7, 500–749: aRR 1.5; 1.2–1.8), received a dual-chamber ICD (aRR 2.0; 1.4–2.7) or CRT-D (aRR 2.6; 1.9–3.4), underwent system upgrade or lead revision (aRR 1.3; 1.0–1.7), had an operator with an annual volume <50 procedures (aRR 1.9; 1.4–2.6), or underwent an emergency, out-of-hours procedure (aRR 1.5; 1.0–2.3). Conclusion CIED complications are more frequent than generally acknowledged. Both patient- and procedure-related predictors may identify patients with a particularly high risk of complications. This information should be taken into account both in individual patient treatment and in the planning of future organization of CIED treatment.

A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

Asthma exacerbations are among the most frequent causes of hospitalization during childhood, but the underlying mechanisms are poorly understood. We performed a genome-wide association study of a specific asthma phenotype characterized by recurrent, severe exacerbations occurring between 2 and 6 years of age in a total of 1,173 cases and 2,522 controls. Cases were identified from national health registries of hospitalization, and DNA was obtained from the Danish Neonatal Screening Biobank. We identified five loci with genome-wide significant association. Four of these, GSDMB, IL33, RAD50 and IL1RL1, were previously reported as asthma susceptibility loci, but the effect sizes for these loci in our cohort were considerably larger than in the previous genome-wide association studies of asthma. We also obtained strong evidence for a new susceptibility gene, CDHR3 (encoding cadherin-related family member 3), which is highly expressed in airway epithelium. These results demonstrate the strength of applying specific phenotyping in the search for asthma susceptibility genes.

Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

The genetic contribution to the variation in human lifespan is ∼25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10−8). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10−36), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

Health of children born to mothers who had preeclampsia: a population-based cohort study

OBJECTIVE We assessed whether preeclampsia correlates with the long-term postnatal health of the offspring. STUDY DESIGN We conducted a population-based cohort study of 1,618,481 singletons born in Denmark (1978-2004) with up to 27 years of follow-up. We used Cox regression to estimate the associations between preeclampsia and long-term health outcomes of the offspring. RESULTS Children born at term exposed to preeclampsia had an increased risk of a variety of diseases, such as endocrine, nutritional, and metabolic diseases (incidence rate ratio, 1.6; 95% confidence interval, 1.5-1.7), and diseases of the blood and blood-forming organs (incidence rate ratio, 1.5; 95% confidence interval, 1.3-1.8). Children born preterm exposed to preeclampsia had a similar pattern of hospitalizations compared with the children born preterm unexposed to preeclampsia, although they had a decreased risk of cerebral palsy (incidence rate ratio, 0.7; 95% confidence interval, 0.6-0.9). CONCLUSION Preeclampsia was associated with an increased risk of being hospitalized for a number of diseases, especially in the children born at term.

Pregnancy outcomes related to gestational weight gain in women defined by their body mass index, parity, height, and smoking status

BACKGROUND Recommendations for gestational weight gain (GWG) account for a womans prepregnancy body mass index (BMI), but other factors may be important. OBJECTIVES The objectives were to investigate whether, within BMI categories, the GWG with the lowest risks to mother and infant varied with parity and to describe these risks in short (<160 cm), young (<20 y), and smoking women. DESIGN Of 27,030 primiparous and 31,407 multiparous women with term births within the Danish National Birth Cohort, self-reported GWG was divided into 6 categories (<5, 5-9, 10-15, 16-19, 20-24, and > or =25 kg). Population-based registers provided information about birth outcomes. GWG-specific absolute adjusted risks for emergency cesarean delivery, birth of a small-for-gestational-age (SGA) or large-for-gestational-age (LGA) infant, and postpartum (6 mo) weight retention (PPWR) were compared across different types of women. RESULTS The risk of SGA decreased with increasing GWG in both parity groups, but SGA risk <10% was reached at 2-3 GWG categories lower in multiparae than in primiparae. An excess risk of LGA was present only in obese primiparae and multiparae, but the PPWR risk increased with increasing GWG irrespective of BMI and parity. Young primiparae had better outcomes than other primiparae. Short women had a higher risk of emergency cesarean delivery that varied minimally with GWG. Smokers had a higher SGA risk and had a PPWR risk similar to that of nonsmokers. CONCLUSIONS The tradeoff in risk between mother and infant is reached at lower GWG in multiparae than in primiparae; therefore, a lower GWG may be needed among multiparae. Differential guidelines seem unnecessary for short or young women or smokers.

Severe obesity in young women and reproductive health: the Danish National Birth Cohort.

Background Little is known about reproductive health in severely obese women. In this study, we present associations between different levels of severe obesity and a wide range of health outcomes in the mother and child. Methods From the Danish National Birth Cohort, we obtained self-reported information about prepregnant body mass index (BMI) for 2451 severely obese women and 2450 randomly selected women from the remaining cohort who served as a comparison group. Information about maternal and infant outcomes was also self-reported or came from registers. Logistic regression was used to estimate the association between different levels of severe obesity and reproductive outcomes. Principal Findings Subfecundity was more frequent in severely obese women, and during pregnancy, they had an excess risk of urinary tract infections, gestational diabetes, preeclampsia and other hypertensive disorders which increased with severity of obesity. They tended to have a higher risk of both pre- and post-term birth, and risk of cesarean and instrumental deliveries increased across obesity categories. After birth, severely obese women more often failed to initiate or sustain breastfeeding. Risk of weight retention 1.5 years after birth was similar to that of other women, but after adjustment for gestational weight gain, the risk was increased, especially in women in the lowest obesity category. In infants, increasing maternal obesity was associated with decreased risk of a low birth weight and increased risk of a high birth weight. Estimates for ponderal index showed the same pattern indicating an increasing risk of neonatal fatness with severity of obesity. Infant obesity measured one year after birth was also increased in children of severely obese mothers. Conclusion Severe obesity is correlated with a substantial disease burden in reproductive health. Although the causal mechanisms remain elusive, these findings are useful for making predictions and planning health care at the individual level.

Selection by socioeconomic factors into the Danish National Birth Cohort

Background Low participation at recruitment to the Danish National Birth Cohort (DNBC) has raised concern about non-participation bias. Objective To study the socioeconomic pattern of participation to the DNBC. Methods Independently of the DNBC, we identified the DNBC source population in two geographical areas of Denmark by means of local birth registers with full coverage. Socioeconomic information came from national registers, and the source population consisted of 48,560 births including 15,290 participating women. For every socioeconomic characteristic, we estimated the prevalence ratio [prevalence (participants)/prevalence (source population)] which corresponds to the relative representation of the group (presented in percentages with 95% confidence intervals). Results The overall participation rate was 31%. Women outside the work force or with no further education than compulsory school were underrepresented in the DNBC by 62% (59%; 64%) and 43% (41%; 45%), respectively. Also, women were underrepresented by 18% (13%; 23%) if they were unemployed, by 22% (20%; 24%) if they were in the lowest income group, 38% (35%; 40%) if they received a high proportion of social benefits, and 28% (24%; 31%) if they were singles. Particularly women with low resources according to two socioeconomic factors were strongly underrepresented, typically by 50–67%. Conclusion Groups with low socioeconomic resources in terms of education, occupation, income and civil status are underrepresented in the DNBC compared to the background population. These discrepancies must be taken into account when results from the DNBC and other cohorts of pregnant women are interpreted—especially when descriptive results are presented.

Genome-Wide Population-Based Association Study of Extremely Overweight Young Adults - The GOYA Study

Background Thirty-two common variants associated with body mass index (BMI) have been identified in genome-wide association studies, explaining ∼1.45% of BMI variation in general population cohorts. We performed a genome-wide association study in a sample of young adults enriched for extremely overweight individuals. We aimed to identify new loci associated with BMI and to ascertain whether using an extreme sampling design would identify the variants known to be associated with BMI in general populations. Methodology/Principal Findings From two large Danish cohorts we selected all extremely overweight young men and women (n = 2,633), and equal numbers of population-based controls (n = 2,740, drawn randomly from the same populations as the extremes, representing ∼212,000 individuals). We followed up novel (at the time of the study) association signals (p<0.001) from the discovery cohort in a genome-wide study of 5,846 Europeans, before attempting to replicate the most strongly associated 28 SNPs in an independent sample of Danish individuals (n = 20,917) and a population-based cohort of 15-year-old British adolescents (n = 2,418). Our discovery analysis identified SNPs at three loci known to be associated with BMI with genome-wide confidence (P<5×10−8; FTO, MC4R and FAIM2). We also found strong evidence of association at the known TMEM18, GNPDA2, SEC16B, TFAP2B, SH2B1 and KCTD15 loci (p<0.001), and nominal association (p<0.05) at a further 8 loci known to be associated with BMI. However, meta-analyses of our discovery and replication cohorts identified no novel associations. Significance Our results indicate that the detectable genetic variation associated with extreme overweight is very similar to that previously found for general BMI. This suggests that population-based study designs with enriched sampling of individuals with the extreme phenotype may be an efficient method for identifying common variants that influence quantitative traits and a valid alternative to genotyping all individuals in large population-based studies, which may require tens of thousands of subjects to achieve similar power.