Taking multi-morbidity into account when attributing DALYs to risk factors: comparing dynamic modeling with the GBD2010 calculation method.

BACKGROUND: Disability Adjusted Life Years (DALYs) quantify the loss of healthy years of life due to dying prematurely and due to living with diseases and injuries. Current methods of attributing DALYs to underlying risk factors fall short on two main points. First, risk factor attribution methods often unjustly apply incidence-based population attributable fractions (PAFs) to prevalence-based data. Second, it mixes two conceptually distinct approaches targeting different goals, namely an attribution method aiming to attribute uniquely to a single cause, and an elimination method aiming to describe a counterfactual situation without exposure. In this paper we describe dynamic modeling as an alternative, completely counterfactual approach and compare this to the approach used in the Global Burden of Disease 2010 study (GBD2010). METHODS: Using data on smoking in the Netherlands in 2011, we demonstrate how an alternative method of risk factor attribution using a pure counterfactual approach results in different estimates for DALYs. This alternative method is carried out using the dynamic multistate disease table model DYNAMO-HIA. We investigate the differences between our alternative method and the method used by the GBD2010 by doing additional analyses using data from a synthetic population in steady state. RESULTS: We observed important differences between the outcomes of the two methods: in an artificial situation where dynamics play a limited role, DALYs are a third lower as compared to those calculated with the GBD2010 method (398,000 versus 607,000 DALYs). The most important factor is newly occurring morbidity in life years gained that is ignored in the GBD2010 approach. Age-dependent relative risks and exposures lead to additional differences between methods as they distort the results of prevalence-based DALY calculations, but the direction and magnitude of the distortions depend on the particular situation. CONCLUSIONS: We argue that the GBD2010 approach is a hybrid of an attributional and counterfactual approach, making the end result hard to understand, while dynamic modelling uses a purely counterfactual approach and thus yields better interpretable results.

Accounting for multimorbidity can affect the estimation of the Burden of Disease: a comparison of approaches.

BACKGROUND: Various Burden of Disease (BoD) studies do not account for multimorbidity in their BoD estimates. Ignoring multimorbidity can lead to inaccuracies in BoD estimations, particularly in ageing populations that include large proportions of persons with two or more health conditions. The objective of this study is to improve BoD estimates for the Netherlands by accounting for multimorbidity. For this purpose, we analyzed different methods for 1) estimating the prevalence of multimorbidity and 2) deriving Disability Weights (DWs) for multimorbidity by using existing data on single health conditions. METHODS: We included 25 health conditions from the Dutch Burden of Disease study that have a high rate of prevalence and that make a large contribution to the total number of Years Lived with a Disability (YLD). First, we analyzed four methods for estimating the prevalence of multimorbid conditions (i.e. independent, independent age- and sex-specific, dependent, and dependent sex- and age-specific). Secondly, we analyzed three methods for calculating the Combined Disability Weights (CDWs) associated with multimorbid conditions (i.e. additive, multiplicative and maximum limit). A combination of these two approaches was used to recalculate the number of YLDs, which is a component of the Disability-Adjusted Life Years (DALY). RESULTS: This study shows that the YLD estimates for 25 health conditions calculated using the multiplicative method for Combined Disability Weights are 5 % lower, and 14 % lower when using the maximum limit method, than when calculated using the additive method. Adjusting for sex- and age-specific dependent co-occurrence of health conditions reduces the number of YLDs by 10 % for the multiplicative method and by 26 % for the maximum limit method. The adjustment is higher for health conditions with a higher prevalence in old age, like heart failure (up to 43 %) and coronary heart diseases (up to 33 %). Health conditions with a high prevalence in middle age, such as anxiety disorders, have a moderate adjustment (up to 13 %). CONCLUSIONS: We conclude that BoD calculations that do not account for multimorbidity can result in an overestimation of the actual BoD. This may affect public health policy strategies that focus on single health conditions if the underlying cost-effectiveness analysis overestimates the intended effects. The methodology used in this study could be further refined to provide greater insight into co-occurrence and the possible consequences of multimorbid conditions in terms of disability for particular combinations of health conditions.

Mumps vaccine effectiveness in primary schools and households, the Netherlands, 2008.

To estimate the mumps vaccine effectiveness (VE) during a large genotype D mumps outbreak, we conducted a cross-sectional study in eight primary schools and associated households in the Netherlands. Questionnaires were used to collect information on the occurrence of mumps. Multivariate analyses were used to estimate VE. Among schoolchildren we estimated the VE against mumps. Among household contacts where the schoolchild was the index case we estimated the VE against mumps and against mumps infectiousness. In total 1175 children and 2281 household contacts participated in the study. The mumps attack rate among schoolchildren was 17%. The mumps VE in schoolchildren was 92% [95% confidence interval (CI) 83-96%] and 93% [85-97%] for one and two doses of the measles, mumps, rubella (MMR) vaccine, respectively. The adjusted mumps VE among household contacts was 67% [65-95%] and 11% [-4 to 88%] against mumps and mumps infectiousness, respectively. Our study indicates that the mumps component of the MMR vaccine offered adequate protection against mumps among schoolchildren. The relatively low VE among household contacts is of concern.

Emergence and epidemic occurrence of enterovirus 68 respiratory infections in The Netherlands in 2010.

Following an increase in detection of enterovirus 68 (EV68) in community surveillance of respiratory infections in The Netherlands in 2010, epidemiological and virological analyses were performed to investigate the possible public health impact of EV68 infections. We retrospectively tested specimens collected from acute respiratory infections surveillance and through three children cohort studies conducted in The Netherlands from 1994 through 2010. A total of 71 of 13,310 (0.5%) specimens were positive for EV68, of which 67 (94%) were from symptomatic persons. Twenty-four (34%) of the EV68 positive specimens were collected during 2010. EV68-positive patients with respiratory symptoms showed significantly more dyspnea, cough and bronchitis than EV68-negative patients with respiratory symptoms. Phylogenetic analysis showed an increased VP1 gene diversity in 2010, suggesting that the increased number of EV68 detections in 2010 reflects a real epidemic. Clinical laboratories should consider enterovirus diagnostics in the differential diagnosis of patients presenting with respiratory symptoms.

CD14 polymorphisms in mother and infant, soluble CD14 in breast milk and atopy development in the infant (KOALA Study).

Different CD14 polymorphisms have been associated with atopic phenotypes in infants. In addition, CD14 genotypes of breastfeeding mothers have been associated with soluble CD14 (sCD14) levels in breast milk. The role of CD14 genotypes of infant and mother and their interaction with sCD14 levels in breast milk in atopy development remain to be established. We aimed to study the associations of CD14 single nucleotide polymorphisms (SNPs), and their interaction with breast milk sCD14, with atopy development until age two. In addition, we assessed whether levels of sCD14 in breast milk associated with SNPs in CD14. Four SNPs in CD14 gene were investigated in 698 infants and 188 mothers. Associations between these SNPs, sCD14 and atopy development were analyzed in multiple logistic or linear regression models. The CD14/-1619 SNP was associated with eczema. CC homozygotes showed a lower risk of eczema vs. TT homozygotes (adjusted odds ratio = 0.56, 95% confidence interval 0.33-0.96) in a co-dominant model. Breast milk sCD14 levels did not significantly modify the effect of the child's CD14 genotype on atopy development (p interaction > or =0.10). Maternal CD14 SNPs were not significantly associated with sCD14 levels in breast milk (anova, p > or = 0.48). We found only an association between CC homozygozity of SNP CD14/-1619 and eczema. Our data did not support a modifying role of breast milk sCD14 levels on the relationship between CD14 genotype and atopy development until age 2 yr.

Age at first introduction of cow milk products and other food products in relation to infant atopic manifestations in the first 2 years of life: the KOALA Birth Cohort Study.

OBJECTIVES: Scientific evidence is scarce about timing of solid-food introduction and its association with the development of atopy. We aimed to evaluate any associations between the introduction of cow milk products/other solid food products and infant atopic manifestations in the second year of life, taking into account reverse causation. METHODS: Data from 2558 infants in an ongoing prospective birth cohort study in the Netherlands were analyzed. Data on the main determinants (introduction of cow milk products and other food products), outcomes (eczema; atopic dermatitis [United Kingdom Working Party criteria]; recurrent wheeze; any sensitization; sensitization against cow milk, hen egg, peanut, and at least 1 inhalant allergen), and confounders were collected by repeated questionnaires at 34 weeks of gestation and 3, 7, 12, and 24 months postpartum. Information on sensitization was gathered by venous blood collections performed during home visits at age 2. Analyses were performed by multiple logistic regression analyses. RESULTS: More delay in introduction of cow milk products was associated with a higher risk for eczema. In addition, a delayed introduction of other food products was associated with an increased risk for atopy development at the age of 2 years. Exclusion of infants with early symptoms of eczema and recurrent wheeze (to avoid reverse causation) did not essentially change our results. DISCUSSION: Delaying the introduction of cow milk or other food products may not be favorable in preventing the development of atopy.

Consumption of organic foods and risk of atopic disease during the first 2 years of life in the Netherlands.

We prospectively investigated whether organic food consumption by infants was associated with developing atopic manifestations in the first 2 years of life. The KOALA Birth Cohort Study in the Netherlands (n 2764) measured organic food consumption, eczema and wheeze in infants until age 2 years using repeated questionnaires. Diet was defined as conventional ( 90 % organic). Venous blood samples taken from 815 infants at 2 years of age were analysed for total and specific IgE. Multivariate logistic regression models were fitted to control for potential confounding factors. Eczema was present in 32 % of infants, recurrent wheeze in 11 % and prolonged wheezing in 5 %. At 2 years of age, 27 % of children were sensitised against at least one allergen. Of all the children, 10 % had consumed a moderately organic diet and 6 % a strictly organic diet. Consumption of organic dairy products was associated with lower eczema risk (OR 0.64 (95 % CI 0.44, 0.93)), but there was no association of organic meat, fruit, vegetables or eggs, or the proportion of organic products within the total diet with the development of eczema, wheeze or atopic sensitisation. Further studies to substantiate these results are warranted.

Breast-feeding duration and infant atopic manifestations, by maternal allergic status, in the first 2 years of life (KOALA study).

OBJECTIVE: To investigate the potential effect of modification by maternal allergic status on the relationship between breast-feeding duration and infant atopic manifestations in the first 2 years of life. STUDY DESIGN: Data from 2705 infants of the KOALA Birth Cohort Study (The Netherlands) were analyzed. The data were collected by repeated questionnaires at 34 weeks of gestation and 3, 7, 12, and 24 months postpartum. Total and specific immunoglobulin E measurements were performed on venous blood samples collected during home visits at age 2 years. Relationships were analyzed using logistic regression analyses. RESULTS: Longer duration of breast-feeding was associated with a lower risk for eczema in infants of mothers without allergy or asthma (P(trend) = .01) and slightly lower risk in those of mothers with allergy but no asthma (P(trend) = .14). There was no such association for asthmatic mothers (P(trend) = .87). Longer breast-feeding duration decreased the risk of recurrent wheeze independent of maternal allergy (P(trend) = .02) or asthma status (P(trend) = .06). CONCLUSIONS: Our findings show that the relationship between breast-feeding and infant eczema in the first 2 years of life is modified by maternal allergic status. The protective effect of breast-feeding on recurrent wheeze may be associated with protection against respiratory infections.

Breastfeeding and infant eczema in the first year of life in the KOALA birth cohort study: a risk period-specific analysis.

OBJECTIVE: We studied the association between breastfeeding and eczema, taking into account the possible influence of reverse causation, with risk period-specific analyses. METHODS: Information on breastfeeding, determinants, and outcomes at 1 year of age was collected with repeated questionnaires for 2405 mother-infant pairs participating in the KOALA (Child, Parent and Health: Lifestyle and Genetic Constitution [in Dutch]) birth cohort study. By using multivariate logistic regression analysis, we compared an overall analysis with risk period-specific analyses. RESULTS: By the age of 1 year, 535 infants (22.2%) had developed eczema. In an overall analysis, we found a weak nonsignificant trend toward a reduced risk of eczema in the first year of life with increasing duration of breastfeeding (lowest risk for those breastfed for > or = 7 months versus never breastfed). In the risk period-specific analysis (confined to infants "at risk" for eczema onset after 3 months of age), no indication for reverse causation was found (results were not very different, compared with the overall analysis). Infants who were breastfed from birth on had a slightly (although not statistically significantly) increased risk for eczema in the first 3 months of life, compared with infants who were formula fed from birth on. CONCLUSIONS: Our results indicated that no strong effect of breastfeeding on eczema in the first year of life was present. This conclusion was strengthened by risk period-specific analysis, which made the influence of reverse causation unlikely.

Early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in the first 2 years of life: the KOALA Birth Cohort Study.

OBJECTIVES: Antibiotic exposure in early life may be associated with atopic disease development either by interfering with bacterial commensal flora or by modifying the course of bacterial infections. We evaluated early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in infancy. METHODS: Information on antibiotic use in the first 6 months and eczema and wheeze until age 2 was collected by repeated questionnaires in 2764 families participating in the KOALA (Child, Parent and Health: Lifestyle and Genetic Constitution [in Dutch]) Birth Cohort Study in The Netherlands. Antibiotic intake was evaluated both as maternal antibiotic use during breastfeeding and infant oral medication. Venous blood samples taken from 815 infants at 2 years of age were analyzed for total and specific immunoglobulin E against common food and inhalant allergens using a radioallergosorbent test. Multivariate logistic regression analysis was used to adjust for confounding factors. RESULTS: During the first 2 years, eczema was present in 32% of all infants, recurrent wheeze in 11%, and prolonged wheezing in 5%. At 2 years old, 27% of children were sensitized against > or = 1 allergen. At 6 months old, 11% had been exposed to antibiotics through breast milk and 20% directly through medication. The risk for recurrent wheeze, and prolonged wheeze was higher in infants directly exposed to antibiotics through medication, also after excluding from the analyses children who wheezed in the same period as an antibiotic had been used (avoiding reverse causation). Antibiotic use through breastfeeding was associated with recurrent wheeze, but prolonged wheeze was not. Eczema and sensitization were not associated with antibiotic exposure. CONCLUSIONS: We demonstrated that early antibiotic use preceded the manifestation of wheeze but not eczema or allergic sensitization during the first 2 years of life. Different biological mechanisms may underlie the etiology of wheeze compared with eczema or sensitization. Antibiotic exposure through breastfeeding enhanced the risk for recurrent wheeze, but this needs further confirmation.

Etiology of atopy in infancy: the KOALA Birth Cohort Study.

The aim of the KOALA Birth Cohort Study in the Netherlands is to identify factors that influence the clinical expression of atopic disease with a main focus on lifestyle (e.g., anthroposophy, vaccinations, antibiotics, dietary habits, breastfeeding and breast milk composition, intestinal microflora composition, infections during the first year of life, and gene-environment interaction). The recruitment of pregnant women started in October 2000. First, participants with 'conventional lifestyles' (n = 2343) were retrieved from an ongoing prospective cohort study (n = 7020) on pregnancy-related pelvic girdle pain. In addition, pregnant women (n = 491) with 'alternative lifestyles' with regard to child rearing practices, dietary habits (organic, vegetarian), vaccination schemes and/or use of antibiotics, were recruited through organic food shops, anthroposophic doctors and midwives, Steiner schools, and dedicated magazines. All participants were enrolled between 14 and 18 wk of gestation and completed an intake questionnaire on family history of atopy and infant care intentions. Documentation of other relevant variables started in the pregnant mother and covered the first and third trimester as well as early childhood by repeated questionnaires at 14-18, 30, and 34 wk of gestation and 3, 7, 12, and 24 months post-partum. A subgroup of participants, including both conventional and alternative lifestyles, was asked to consent to maternal blood sampling, breast milk and a faecal sample of the infant at 1 month post-partum, capillary blood at age 1 yr, venous blood and observation of manifestation of atopic dermatitis during home visits at the age of 2 yr (using the UK working party criteria and the severity scoring of atopic dermatitis index), and buccal swabs for DNA isolation from child-parent trios. From the start, ethical approval and informed consent procedures included gene-environment interaction studies. Follow-up at 3 and 7 months post-partum was completed with high response rates (respectively 90% and 88% in the conventional group, and 97% and 97% in the alternative group). The home visits at 2 yr of age will be completed in 2005. Preliminary results show that we have succeeded in recruiting a large population with various lifestyle choices with a fairly large contrast with regard to dietary habits (including organic foods, vegetarian diet), vaccination schemes and/or use of antibiotics. We have also been able to collect a large number of faecal samples (n = 1176) and capillary blood samples at age 1 yr (n = 956). Furthermore, a large proportion of the participants have consented with genetic studies. Mid 2006 we expect to report our first results on the relationship between the various exposures in early life and childhood atopy. An outline of the focus and design of the KOALA Birth Cohort Study is presented.