Håkon K. Gjessing

Self-selection and bias in a large prospective pregnancy cohort in Norway.

Self-selection in epidemiological studies may introduce selection bias and influence the validity of study results. To evaluate potential bias due to self-selection in a large prospective pregnancy cohort in Norway, the authors studied differences in prevalence estimates and association measures between study participants and all women giving birth in Norway. Women who agreed to participate in the Norwegian Mother and Child Cohort Study (43.5% of invited; n = 73 579) were compared with all women giving birth in Norway (n = 398 849) using data from the population-based Medical Birth Registry of Norway in 2000-2006. Bias in the prevalence of 23 exposure and outcome variables was measured as the ratio of relative frequencies, whereas bias in exposure-outcome associations of eight relationships was measured as the ratio of odds ratios. Statistically significant relative differences in prevalence estimates between the cohort participants and the total population were found for all variables, except for maternal epilepsy, chronic hypertension and pre-eclampsia. There was a strong under-representation of the youngest women (<25 years), those living alone, mothers with more than two previous births and with previous stillbirths (relative deviation 30-45%). In addition, smokers, women with stillbirths and neonatal death were markedly under-represented in the cohort (relative deviation 22-43%), while multivitamin and folic acid supplement users were over-represented (relative deviation 31-43%). Despite this, no statistically relative differences in association measures were found between participants and the total population regarding the eight exposure-outcome associations. Using data from the Medical Birth Registry of Norway, this study suggests that prevalence estimates of exposures and outcomes, but not estimates of exposure-outcome associations are biased due to self-selection in the Norwegian Mother and Child Cohort Study.

Birthweight by gestational age in Norway

Objective. To describe birthweight by gestational age in Norway for the period 1967–1998, evaluate secular trends and provide new standards for small for gestational age for 16 to 44 weeks of gestation.

Fetal and maternal contributions to risk of pre-eclampsia: population based study

Abstract Objective: To use familial patterns of recurrence of pre-eclampsia to investigate whether paternal genes expressed in the fetus contribute to the mothers risk of pre-eclampsia and whether mothers susceptibility to pre-eclampsia is related to maternal inheritance by mitochondrial DNA. Design: Linked data on pregnancies of different women who had children with the same father, and subsequently linked data on pregnancies of half sisters who either had same mother and different fathers or had same father and different mothers. Setting: Population based data from the Medical Birth Registry of Norway covering all births since 1967 (about 1.7 million) and the Norwegian Central Population Register. Main outcome measures: Relative risk of pre-eclampsia after a previous pre-eclamptic pregnancy in the family. Relative risks approximated by odds ratios. Results: If a woman becomes pregnant by a man who has already fathered a pre-eclamptic pregnancy in a different woman her risk of developing pre-eclampsia is 1.8 (95% confidence interval 1.2 to 2.6). If the woman has a half sister who had pre-eclampsia and with whom she shares the same mother but different fathers the risk of pre-eclampsia is 1.6 (0.9 to2.6). If the two sisters have the same father but different mothers the risk is 1.8 (1.01 to 2.9). Conclusions: Both the mother and the fetus contribute to the risk of pre-eclampsia, the contribution of the fetus being affected by paternal genes. Mitochondrial genes, which are transmitted by mothers, do not seem to contribute to the risk. Key messages Paternal genes in the fetus may contribute substantially to a pregnant womans risk of pre-eclampsia The role of the fetus may be as important as that of the mother Purely maternal inheritance (specifically by mitochondrial DNA) is probably not involved in pre-eclampsia Search for specific genes that predispose for pre-eclampsia should include the fetus as well as the mother

Survival and Event History Analysis

An introduction to survival and event history analysis.- Stochastic processes in event history analysis.- Nonparametric analysis of survival and event history data.- Regression models.- Parametric counting process models.- Unobserved heterogeneity: The odd effects of frailty.- Multivariate frailty models.- Marginal and dynamic models for recurrent events and clustered survival data.- Causality.- First passage time models: Understanding the shape of the hazard rate.- Diffusion and L#x00E9 vy process models for dynamic frailty.

Risk of Fetal Death after Pandemic Influenza Virus Infection or Vaccination

BACKGROUND During the 2009 influenza A (H1N1) pandemic, pregnant women were at risk for severe influenza illness. This concern was complicated by questions about vaccine safety in pregnant women that were raised by anecdotal reports of fetal deaths after vaccination. METHODS We explored the safety of influenza vaccination of pregnant women by linking Norwegian national registries and medical consultation data to determine influenza diagnosis, vaccination status, birth outcomes, and background information for pregnant women before, during, and after the pandemic. We used Cox regression models to estimate hazard ratios for fetal death, with the gestational day as the time metric and vaccination and pandemic exposure as time-dependent exposure variables. RESULTS There were 117,347 eligible pregnancies in Norway from 2009 through 2010. Fetal mortality was 4.9 deaths per 1000 births. During the pandemic, 54% of pregnant women in their second or third trimester were vaccinated. Vaccination during pregnancy substantially reduced the risk of an influenza diagnosis (adjusted hazard ratio, 0.30; 95% confidence interval [CI], 0.25 to 0.34). Among pregnant women with a clinical diagnosis of influenza, the risk of fetal death was increased (adjusted hazard ratio, 1.91; 95% CI, 1.07 to 3.41). The risk of fetal death was reduced with vaccination during pregnancy, although this reduction was not significant (adjusted hazard ratio, 0.88; 95% CI, 0.66 to 1.17). CONCLUSIONS Pandemic influenza virus infection in pregnancy was associated with an increased risk of fetal death. Vaccination during pregnancy reduced the risk of an influenza diagnosis. Vaccination itself was not associated with increased fetal mortality and may have reduced the risk of influenza-related fetal death during the pandemic. (Funded by the Norwegian Institute of Public Health.).

Paternal contribution to birth weight

STUDY OBJECTIVE Understanding causes of variation in birth weight has been limited by lack of sufficient sets of data that include paternal birth weight. The objective was to estimate risks of low birth weight dependent on parental birth weights and to estimate father-mother-offspring correlations for birth weight to explain the variability in birth weight in terms of effects of genes and environmental factors. DESIGN A family design, using trios of father-mother-firstborn child. SETTING The complete birth population in Norway 1967–98. PARTICIPANTS 67 795 families. MAIN RESULTS The birth weight correlations were 0.226 for mother-child and 0.126 for father-child. The spousal correlation was low, 0.020. The relative risk of low birth weight in the first born child was 8.2 if both parents were low birth weight themselves, with both parents being above 4 kg as the reference. The estimate of heritability is about 0.25 for birth weight, under the assumption that cultural transmission on the paternal side has no effect on offspring prenatal growth. CONCLUSIONS Paternal birth weight is a significant and independent predictor of low birth weight in offspring. The estimate of the heritability of birth weight in this study is lower than previously estimated from data within one generation in the Norwegian population.

Optimal choice of dividend barriers for a risk process with stochastic return on investments

Abstract We consider a risk process with stochastic return on investments and we are interested in expected present value of all dividends paid until ruin occurs when the company uses a simple barrier strategy, i.e. when it pays dividends whenever its surplus reaches a level b . It is shown that given the barrier b , this expected value can be found by solving a boundary value problem for an integro-differential equation. The solution is then found in two special cases; when return on investments is constant and the surplus generating process is compound Poisson with exponentially distributed claims, and also when both return on investments as well as the surplus generating process are Brownian motions with drift. Also in this latter case we are able to find the optimal barrier b * , i.e. the barrier that gives the highest expected present value of dividends. Parallell with this we treat the problem of finding the Laplace transform of the distribution of the time to ruin when a barrier strategy is employed, noting that the probability of eventual ruin is 1 in this case. The paper ends with a short discussion of the same problems when a time dependent barrier is employed.

Errors in gestational age : Evidence of bleeding early in pregnancy

OBJECTIVES This study explored the extent of errors in gestational age as ascertained by last menstrual period. METHODS More than 1.5 million birth records (covering the years 1967-1994) from the population-based Medical Birth Registry of Norway were used to study variation in gestational age within strata of birthweight. RESULTS Within 100-g strata of birthweight, it was found that the observed gestational age distribution could be divided into 3 distinct underlying distributions separated by approximately 4 weeks. This pattern was present through all birthweight strata, from 200 g up to 4700 g. In addition, the apparent misclassification causing a gestational age 4 weeks too short was much more common among low-birthweight births than among heavier births. CONCLUSIONS The separation of the gestational age distributions by intervals of close to 4 weeks suggests that errors in gestational age measurements are caused by factors related to menstrual bleeding. Furthermore, there is evidence for a strong relation between bleeding at the time of the next menstrual period after conception and low birthweight. This conclusion should be approached with caution because of the retrospective nature of the data.

Mortality after total hip replacement: 0-10-year follow-up of 39,543 patients in the Norwegian Arthroplasty Register

We have studied the mortality after total hip replacement (THR) of 39,543 patients, having a mean age of 69 years, who were reported to the Norwegian Arthroplasty Register. The median follow-up time was 5.2 (0-10.4) years. 323 of 6201 deaths occurred during the first 60 postoperative days. The patient mortality was compared with the mortality in the Norwegian population, using standardized mortality ratios (SMR). The SMRs were compared and adjusted for age, gender, and other possible confounders in a Cox regression model incorporating the population mortality. We observed a lower mortality in patients with THR than in the Norwegian population (8-year patient mortality was 25%, versus 30% in the corresponding Norwegian population. SMR = 0.81). There was an increased standardized mortality ratio in patients less than 50 years (SMR = 2.50), patients 50-59 years (SMR = 1.16), patients with THR due to rheumatoid arthritis (SMR = 1.48), and patients with femoral neck fracture (SMR = 1.11). The SMR decreased with increasing age at the time of THR surgery. After revision surgery, the SMR was similar to that after the first primary operation, whereas a second primary operation in the opposite hip was associated with a further reduction in the SMR (SMR = 0.65). During the first 60 postoperative days, all patient categories had a higher mortality than the general population (0.8% mortality, SMR = 1.39).

Genetic variants in IRF6 and the risk of facial clefts: single-marker and haplotype-based analyses in a population-based case-control study of facial clefts in Norway.

Mutations in the gene encoding interferon regulatory factor 6 (IRF6) underlie a common form of syndromic clefting known as Van der Woude syndrome. Lip pits and missing teeth are the only additional features distinguishing the syndrome from isolated clefts. Van der Woude syndrome, therefore, provides an excellent model for studying the isolated forms of clefting. From a population‐based case‐control study of facial clefts in Norway (1996–2001), we selected 377 cleft lip with or without cleft palate (CL/P), 196 cleft palate only (CPO), and 763 control infant‐parent triads for analysis. We genotyped six single nucleotide polymorphisms within the IRF6 locus and estimated the relative risks (RR) conferred on the child by alleles and haplotypes of the child and of the mother. On the whole, there were strong statistical associations with CL/P but not CPO in our data. In single‐marker analyses, mothers with a double‐dose of the ‘a’‐allele at rs4844880 had an increased risk of having a child with CL/P (RR=1.85, 95% confidence interval: 1.04–3.25; P=0.036). An RR of 0.38 (95% confidence interval: 0.16–0.92; P=0.031) was obtained when the child carried a single‐dose of the ‘a’‐allele at rs2235371 (the p.V274I polymorphism). The P‐value for the overall test was <0.001. In haplotype analyses, several of the fetal and maternal haplotype relative risks were statistically significant individually but were not strong enough to show up on the overall test (P=0.113). Taken together, these findings further support a role for IRF6 variants in clefting of the lip and provide specific risk estimates in a Norwegian population. Genet. Epidemiol. 2008.