Int. J. Epidemiol. Advance Access published October 29, 2014 International Journal of Epidemiology, 2014, 1–10 doi: 10.1093/ije/dyu204 Original article
Original article
Maternal age at childbirth and risk for ADHD in offspring: a population-based cohort study Downloaded from http://ije.oxfordjournals.org/ at Ondokuz Mayis University on November 7, 2014
Zheng Chang,1,2* Paul Lichtenstein,1 Brian M D’Onofrio,3 Catarina Almqvist,1,4 Ralf Kuja-Halkola,1 Arvid Sjo¨lander1 and Henrik Larsson1 1
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, Department of Psychiatry, University of Oxford, Oxford, UK, 3Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA and 4Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden 2
*Corresponding author. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, 17177 Stockholm, Sweden. E-mail: [email protected] Accepted 19 September 2014
Abstract Background: Women who give birth at younger ages (e.g. teenage mothers) are more likely to have children who exhibit behaviour problems, such as attention-deficit/ hyperactivity disorder (ADHD). However, it is not clear whether young maternal age is causally associated with poor offspring outcomes or confounded by familial factors. Methods: The association between early maternal age at childbirth and offspring ADHD was studied using data from Swedish national registers. The sample included all children born in Sweden between 1988 and 2003 (N ¼ 1 495 543), including 30 674 children with ADHD. We used sibling- and cousin-comparisons to control for unmeasured genetic and environmental confounding. Further, we used a children-of-siblings model to quantify the genetic and environmental contribution to the association between maternal age and offspring ADHD. Results: Maternal age at first birth (MAFB) was associated with offspring ADHD. Teenage childbirth (¼4th Maternal age at birth (mean y 6 SD) Maternal age at first birth (mean y 6 SD) Paternal age at birth (%) ¼35 y Missing Calendar year of birth (%) 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
1 495 543
988 625
383 511
51.2 48.8
51.3 48.7
51.2 48.8
41.9 36.2 15.2 6.7 29.3 6 5.1 26.0 6 4.7
36.8 41.6 14.9 6.7 29.0 6 4.7 26.0 6 4.3
40.7 37.3 15.8 6.2 29.1 6 4.8 26.0 6 4.5
0.6 9.3 28.9 32.3 28.3 0.6
0.4 9.1 31.3 33.5 25.5 0.2
0.5 9.7 31.5 33.5 24.6 0.2
6.7 7.0 7.4 7.4 7.3 7.0 6.7 6.2 5.8 5.4 5.2 5.2 5.4 5.5 5.8 6.0
5.1 5.5 6.9 7.8 8.2 8.1 7.8 7.2 6.7 6.3 6.0 5.9 5.7 4.9 4.0 3.9
6.7 7.2 7.8 8.0 7.9 7.4 7.1 6.4 5.9 5.5 5.2 5.1 5.1 5.0 4.9 4.8
Table 2. Association between maternal age at each birth (MAEB) and offspring ADHD (hazard ratios with 95% confidence intervals) MAEB
Model 1a
Model 2b
Model 3c
Model 4d
Binarye Continuous
2.24 (2.12–2.36) 1.06 (1.05–1.06)
1.57 (1.48–1.67) 1.05 (1.04–1.05)
0.90 (0.84–0.96) 0.99 (0.99–1.00)
0.81 (0.71–0.94) 0.98 (0.97–0.99)
a
Population-wide association, adjusted for offspring’s sex, birth order and birth year in categories. In addition to Model 1, adjusted for paternal age at childbirth in categories. c In addition to Model 2, adjusted for MAFB. d Sibling-comparison, adjusted for unmeasured genetic and environmental factors shared by siblings and measured covariates. e MAEB < 20 y. b
The children-of-siblings model Table 4 shows the genetic and environmental influence on MAFB, offspring ADHD and the association between them. MAFB showed a moderate heritability, with genetic
influence explaining 49% of the variance. ADHD showed a high heritability, with genetic influence explaining 73% of the variance. There was a significant phenotypic correlation between MAFB and ADHD (r ¼ 0.12).
Downloaded from http://ije.oxfordjournals.org/ at Ondokuz Mayis University on November 7, 2014
Variables
International Journal of Epidemiology, 2014, Vol. 0, No. 0
7
The phenotypic correlation between MAFB and offspring ADHD was mainly explained by the genetic correlation (rA ¼ 0.40) between MAFB and ADHD. This result confirmed and extended the findings from the cousincomparison in suggesting that the association between MAFB and offspring ADHD was not causal and was, instead, explained largely or entirely through genetic factors that influence the liability to both MAFB and ADHD.
Discussion
Table 3. Association between maternal age at first birth (MAFB) and offspring ADHD (hazard ratios with 95% confidence intervals) MAFB
Population-widea
Cousin-comparisonb
Binaryc Continuous
1.78 (1.72–1.84) 1.07 (1.06–1.07)
1.33 (1.18–1.50) 1.03 (1.02–1.04)
a
Population-wide association, adjusted for offspring’s sex, birth order in categories, birth year in categories and paternal age at childbirth in categories. b Cousin-comparison, adjusted for unmeasured genetic and environmental factors shared by cousins and measured covariates. c MAEB < 20 y.
Table 4. Genetic and environmental influence (with 95% confidence intervals) on the maternal age at first birth (MAFB), offspring ADHD and the association between them Genetic and environmental influence on MAFB and ADHD A% MAFB ADHD
Cross-phenotype correlationa Contribution to phenotypic correlationb
T%
N%
E%
49 (45–54) 6.7 (4.5–8.8) 44 (42–46) 73 (63–85) 5.9 (2.6–9.5) 2.1 (1.5–3.4) 19 (14–26) Genetic and environmental influence onthe association between MAFB and ADHD rA rT rN Phenotypic correlation 0.40 (0.24–0.60) 0.17 (0.42–0.78) 0.13 (0.99–0.99) 0.12 0.01 0.01 0.12
A, additive genetic; T, extended-family environmental; N, nuclear-family environmental; E, unique environmental influence. a rA, rT, rN, cross-phenotype correlation of each variance component (A, T, N). b Phenotypic correlation explained by additive genetic correlation is calculated as 0.5*HAMAFB*HAADHD*rA, by extended-family environmental correlation HTMAFB*HTADHD*rT and by nuclear-family environmental correlation HNMAFB*HNADHD*rN. The sum of the three components is the phenotypic correlation.
Downloaded from http://ije.oxfordjournals.org/ at Ondokuz Mayis University on November 7, 2014
The current study examined the association between early maternal age at childbirth and offspring ADHD, in a large population-based cohort with family-based designs. Our results support two main conclusions. First, maternal age at first birth predicted offspring ADHD. Thus, all offspring born to mothers who began childbearing early were at increased risk of ADHD. Second, the association between MAFB and offspring ADHD was mainly explained by genetic confounding: that is, genetic factors transmitted from mothers to children contribute to both age at childbirth in mothers and ADHD in offspring.
In line with previous research,5,7,8 we found that MAEB was associated with an increased risk of offspring ADHD. However, the increased risk disappeared when controlling for MAFB or conducting sibling-comparison, suggesting that the population-wide association between maternal age and offspring ADHD was due to risk factors at a family level. Similar findings have been observed for other behavioural outcomes.9,10 Thus, all offspring born to mothers who began childbearing early were at increased risk of ADHD, which may have important implications for the planning of family-based prevention efforts. If anything, the within-family analyses were indicative of a protective effect of MAEB. There are at least two alternative explanations to this finding. Advancing maternal age might increase the risk of neurodevelopmental disorders, as suggested by a meta-analysis on maternal age and autism.34 Alternatively, because of the correlation between maternal age and paternal age, the protective effect could also be explained by residual confounding of advancing paternal age, which has been reported as a risk factor for psychiatric disorders.8,35 Further research is required to explore whether advancing maternal age or paternal age increases the risk of ADHD. Family-based designs (e.g. sibling- and cousincomparisons) have been used to test causal hypotheses about putative environmental risk factors,9,10,36 but no previous study with such designs has investigated the association between young maternal age and offspring ADHD. Compared with population-wide estimates, the association between MAFB and offspring ADHD substantially decreased in the cousin comparisons, suggesting that the association was largely explained by unmeasured familial factors. Similar results were found in a study on maternal age and cognitive test score.10 In contrast, other studies have found support for a causal mechanism underlying the association between MAFB and offspring disruptive
8
effect of maternal age on ADHD. Second, teenage childbirth is relatively rare in Sweden compared with the USA and other countries.26 Therefore, generalizations from these results to other countries should be made with caution. Third, although the cousin-comparison partially controls for some aspects of the environment shared within extended families, the fact that there is no measured information on the extent to which the cousins share an environment should be considered as a limitation. Fourth, the CoS model assumed equal environment among all types of relative groups (except for mothers with paternal halfsisters). This means that MZ twins and their family would spend similar amounts of time together as the families of DZ twins and full sisters.39 Fifth, the model also assumed no assortative mating. In case of assortative mating, the genetic confounding might also be explained by the father’s genetic risk. As such, additional research is needed to explore this question using other study designs. To conclude, the current study found that MAFB predicted offspring ADHD, and all offspring born to mothers who began childbearing early were at increased risk of ADHD. The association between young maternal age and offspring ADHD was mainly explained by genetic confounding. Teenage childbearing is internationally recognized as a public health issue with adverse consequences for both young mothers and their children.26 Although young maternal age itself does not cause offspring ADHD, it is an important risk marker for all children born to young mothers. Our results suggested that public policy initiatives should aim not only to promote later childbearing in the population, but also identify individual at-risk mothers and their children who may need support. Our findings are also likely to contribute to the understanding of the aetiology of ADHD. What is usually considered as an environmental risk factor (teenage childbearing) is likely a marker of genetic predisposition. Our study highlights the importance of using family-based designs when trying to understand how early life circumstances affect child development, and underscores the need for additional research on this topic to ensure that prevention efforts and public policy are evidence based.
Supplementary Data Supplementary data are available at IJE online.
Funding This study was supported in part by the Swedish Research Council (2010-3184; 2011-2492), the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM, 340-20135867), the Swedish Council for Working Life and Social Research (2006-1625) and the National Institute of Child Health and Human Development (HD061817).
Downloaded from http://ije.oxfordjournals.org/ at Ondokuz Mayis University on November 7, 2014
behaviors and criminal convictions (including one Swedish study).9,36 These different results might suggest that MAFB is one aetiological factor that differentiates ADHD from other externalizing disorders. This interpretation is consistent with a meta-analysis showing that shared environmental influences accounted for 10–19% of the variance in externalizing disorders, but in contrast had a very limited impact on ADHD.37 To further understand the mechanism of the familial influences on the association between MAFB and offspring ADHD, we used a CoS model which was designed to explore the effect of a risk factor at the family level. We found that both MAFB and ADHD were heritable, and the association between them was mainly explained by shared genetic influences, which suggests that genetic factors influencing MAFB were passed down from parents to their offspring and accounted for most of the risk of ADHD. These results are consistent with findings from a recent twin study showing that the association between ADHD and adolescent sexual risk behaviour is due to genetic factors.38 Determination of causal connections between parental characteristics and child outcomes is one of the key questions in the field of developmental psychopathology.39,40 The sibling- and cousin-comparisons provided insight into whether familial factors account for the association between parental characteristics and child outcomes, and had the important advantage of conceptual clarity.18 However, they cannot quantify the magnitude of different processes explaining the observed association. The CoS model used in this study provided a powerful quantitative approach to disentangle and quantify the underlying processes explaining the observed association, which had several advantages. First, the model used multiple relative groups, thus increasing analytical power and improving generalizability. Second, more than one child from each nuclear family can be included in the model. Therefore, it was possible to study family-level risk factors that influenced all children in the same family. Third, the model can quantify the degree to which the association between parental characteristics and child outcomes is consistent with a causal influence, or instead is due to confounding factors (environmental or genetic). The results in this study should also be considered in the context of its limitations. First, although recent validation checks of ADHD diagnoses in Swedish registers indicated low numbers of false-positives, our case identification strategy could not avoid false-negatives, especially for older children in this cohort. The potential misclassification should be non-differential for population-based comparison, and would lead to null findings; hence, our findings are probably conservative estimates of the actual
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International Journal of Epidemiology, 2014, Vol. 0, No. 0
Conflict of interest: Dr H. Larsson has served as a speaker for Eli Lilly & Co., and his association with Eli Lilly was not related to this publication in any way. All other authors declared no conflicts of interest.
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Original article
Maternal age at childbirth and risk for ADHD in offspring: a population-based cohort study Downloaded from http://ije.oxfordjournals.org/ at Ondokuz Mayis University on November 7, 2014
Zheng Chang,1,2* Paul Lichtenstein,1 Brian M D’Onofrio,3 Catarina Almqvist,1,4 Ralf Kuja-Halkola,1 Arvid Sjo¨lander1 and Henrik Larsson1 1
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, Department of Psychiatry, University of Oxford, Oxford, UK, 3Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA and 4Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden 2
*Corresponding author. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, 17177 Stockholm, Sweden. E-mail: [email protected] Accepted 19 September 2014
Abstract Background: Women who give birth at younger ages (e.g. teenage mothers) are more likely to have children who exhibit behaviour problems, such as attention-deficit/ hyperactivity disorder (ADHD). However, it is not clear whether young maternal age is causally associated with poor offspring outcomes or confounded by familial factors. Methods: The association between early maternal age at childbirth and offspring ADHD was studied using data from Swedish national registers. The sample included all children born in Sweden between 1988 and 2003 (N ¼ 1 495 543), including 30 674 children with ADHD. We used sibling- and cousin-comparisons to control for unmeasured genetic and environmental confounding. Further, we used a children-of-siblings model to quantify the genetic and environmental contribution to the association between maternal age and offspring ADHD. Results: Maternal age at first birth (MAFB) was associated with offspring ADHD. Teenage childbirth (¼4th Maternal age at birth (mean y 6 SD) Maternal age at first birth (mean y 6 SD) Paternal age at birth (%) ¼35 y Missing Calendar year of birth (%) 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
1 495 543
988 625
383 511
51.2 48.8
51.3 48.7
51.2 48.8
41.9 36.2 15.2 6.7 29.3 6 5.1 26.0 6 4.7
36.8 41.6 14.9 6.7 29.0 6 4.7 26.0 6 4.3
40.7 37.3 15.8 6.2 29.1 6 4.8 26.0 6 4.5
0.6 9.3 28.9 32.3 28.3 0.6
0.4 9.1 31.3 33.5 25.5 0.2
0.5 9.7 31.5 33.5 24.6 0.2
6.7 7.0 7.4 7.4 7.3 7.0 6.7 6.2 5.8 5.4 5.2 5.2 5.4 5.5 5.8 6.0
5.1 5.5 6.9 7.8 8.2 8.1 7.8 7.2 6.7 6.3 6.0 5.9 5.7 4.9 4.0 3.9
6.7 7.2 7.8 8.0 7.9 7.4 7.1 6.4 5.9 5.5 5.2 5.1 5.1 5.0 4.9 4.8
Table 2. Association between maternal age at each birth (MAEB) and offspring ADHD (hazard ratios with 95% confidence intervals) MAEB
Model 1a
Model 2b
Model 3c
Model 4d
Binarye Continuous
2.24 (2.12–2.36) 1.06 (1.05–1.06)
1.57 (1.48–1.67) 1.05 (1.04–1.05)
0.90 (0.84–0.96) 0.99 (0.99–1.00)
0.81 (0.71–0.94) 0.98 (0.97–0.99)
a
Population-wide association, adjusted for offspring’s sex, birth order and birth year in categories. In addition to Model 1, adjusted for paternal age at childbirth in categories. c In addition to Model 2, adjusted for MAFB. d Sibling-comparison, adjusted for unmeasured genetic and environmental factors shared by siblings and measured covariates. e MAEB < 20 y. b
The children-of-siblings model Table 4 shows the genetic and environmental influence on MAFB, offspring ADHD and the association between them. MAFB showed a moderate heritability, with genetic
influence explaining 49% of the variance. ADHD showed a high heritability, with genetic influence explaining 73% of the variance. There was a significant phenotypic correlation between MAFB and ADHD (r ¼ 0.12).
Downloaded from http://ije.oxfordjournals.org/ at Ondokuz Mayis University on November 7, 2014
Variables
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7
The phenotypic correlation between MAFB and offspring ADHD was mainly explained by the genetic correlation (rA ¼ 0.40) between MAFB and ADHD. This result confirmed and extended the findings from the cousincomparison in suggesting that the association between MAFB and offspring ADHD was not causal and was, instead, explained largely or entirely through genetic factors that influence the liability to both MAFB and ADHD.
Discussion
Table 3. Association between maternal age at first birth (MAFB) and offspring ADHD (hazard ratios with 95% confidence intervals) MAFB
Population-widea
Cousin-comparisonb
Binaryc Continuous
1.78 (1.72–1.84) 1.07 (1.06–1.07)
1.33 (1.18–1.50) 1.03 (1.02–1.04)
a
Population-wide association, adjusted for offspring’s sex, birth order in categories, birth year in categories and paternal age at childbirth in categories. b Cousin-comparison, adjusted for unmeasured genetic and environmental factors shared by cousins and measured covariates. c MAEB < 20 y.
Table 4. Genetic and environmental influence (with 95% confidence intervals) on the maternal age at first birth (MAFB), offspring ADHD and the association between them Genetic and environmental influence on MAFB and ADHD A% MAFB ADHD
Cross-phenotype correlationa Contribution to phenotypic correlationb
T%
N%
E%
49 (45–54) 6.7 (4.5–8.8) 44 (42–46) 73 (63–85) 5.9 (2.6–9.5) 2.1 (1.5–3.4) 19 (14–26) Genetic and environmental influence onthe association between MAFB and ADHD rA rT rN Phenotypic correlation 0.40 (0.24–0.60) 0.17 (0.42–0.78) 0.13 (0.99–0.99) 0.12 0.01 0.01 0.12
A, additive genetic; T, extended-family environmental; N, nuclear-family environmental; E, unique environmental influence. a rA, rT, rN, cross-phenotype correlation of each variance component (A, T, N). b Phenotypic correlation explained by additive genetic correlation is calculated as 0.5*HAMAFB*HAADHD*rA, by extended-family environmental correlation HTMAFB*HTADHD*rT and by nuclear-family environmental correlation HNMAFB*HNADHD*rN. The sum of the three components is the phenotypic correlation.
Downloaded from http://ije.oxfordjournals.org/ at Ondokuz Mayis University on November 7, 2014
The current study examined the association between early maternal age at childbirth and offspring ADHD, in a large population-based cohort with family-based designs. Our results support two main conclusions. First, maternal age at first birth predicted offspring ADHD. Thus, all offspring born to mothers who began childbearing early were at increased risk of ADHD. Second, the association between MAFB and offspring ADHD was mainly explained by genetic confounding: that is, genetic factors transmitted from mothers to children contribute to both age at childbirth in mothers and ADHD in offspring.
In line with previous research,5,7,8 we found that MAEB was associated with an increased risk of offspring ADHD. However, the increased risk disappeared when controlling for MAFB or conducting sibling-comparison, suggesting that the population-wide association between maternal age and offspring ADHD was due to risk factors at a family level. Similar findings have been observed for other behavioural outcomes.9,10 Thus, all offspring born to mothers who began childbearing early were at increased risk of ADHD, which may have important implications for the planning of family-based prevention efforts. If anything, the within-family analyses were indicative of a protective effect of MAEB. There are at least two alternative explanations to this finding. Advancing maternal age might increase the risk of neurodevelopmental disorders, as suggested by a meta-analysis on maternal age and autism.34 Alternatively, because of the correlation between maternal age and paternal age, the protective effect could also be explained by residual confounding of advancing paternal age, which has been reported as a risk factor for psychiatric disorders.8,35 Further research is required to explore whether advancing maternal age or paternal age increases the risk of ADHD. Family-based designs (e.g. sibling- and cousincomparisons) have been used to test causal hypotheses about putative environmental risk factors,9,10,36 but no previous study with such designs has investigated the association between young maternal age and offspring ADHD. Compared with population-wide estimates, the association between MAFB and offspring ADHD substantially decreased in the cousin comparisons, suggesting that the association was largely explained by unmeasured familial factors. Similar results were found in a study on maternal age and cognitive test score.10 In contrast, other studies have found support for a causal mechanism underlying the association between MAFB and offspring disruptive
8
effect of maternal age on ADHD. Second, teenage childbirth is relatively rare in Sweden compared with the USA and other countries.26 Therefore, generalizations from these results to other countries should be made with caution. Third, although the cousin-comparison partially controls for some aspects of the environment shared within extended families, the fact that there is no measured information on the extent to which the cousins share an environment should be considered as a limitation. Fourth, the CoS model assumed equal environment among all types of relative groups (except for mothers with paternal halfsisters). This means that MZ twins and their family would spend similar amounts of time together as the families of DZ twins and full sisters.39 Fifth, the model also assumed no assortative mating. In case of assortative mating, the genetic confounding might also be explained by the father’s genetic risk. As such, additional research is needed to explore this question using other study designs. To conclude, the current study found that MAFB predicted offspring ADHD, and all offspring born to mothers who began childbearing early were at increased risk of ADHD. The association between young maternal age and offspring ADHD was mainly explained by genetic confounding. Teenage childbearing is internationally recognized as a public health issue with adverse consequences for both young mothers and their children.26 Although young maternal age itself does not cause offspring ADHD, it is an important risk marker for all children born to young mothers. Our results suggested that public policy initiatives should aim not only to promote later childbearing in the population, but also identify individual at-risk mothers and their children who may need support. Our findings are also likely to contribute to the understanding of the aetiology of ADHD. What is usually considered as an environmental risk factor (teenage childbearing) is likely a marker of genetic predisposition. Our study highlights the importance of using family-based designs when trying to understand how early life circumstances affect child development, and underscores the need for additional research on this topic to ensure that prevention efforts and public policy are evidence based.
Supplementary Data Supplementary data are available at IJE online.
Funding This study was supported in part by the Swedish Research Council (2010-3184; 2011-2492), the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM, 340-20135867), the Swedish Council for Working Life and Social Research (2006-1625) and the National Institute of Child Health and Human Development (HD061817).
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behaviors and criminal convictions (including one Swedish study).9,36 These different results might suggest that MAFB is one aetiological factor that differentiates ADHD from other externalizing disorders. This interpretation is consistent with a meta-analysis showing that shared environmental influences accounted for 10–19% of the variance in externalizing disorders, but in contrast had a very limited impact on ADHD.37 To further understand the mechanism of the familial influences on the association between MAFB and offspring ADHD, we used a CoS model which was designed to explore the effect of a risk factor at the family level. We found that both MAFB and ADHD were heritable, and the association between them was mainly explained by shared genetic influences, which suggests that genetic factors influencing MAFB were passed down from parents to their offspring and accounted for most of the risk of ADHD. These results are consistent with findings from a recent twin study showing that the association between ADHD and adolescent sexual risk behaviour is due to genetic factors.38 Determination of causal connections between parental characteristics and child outcomes is one of the key questions in the field of developmental psychopathology.39,40 The sibling- and cousin-comparisons provided insight into whether familial factors account for the association between parental characteristics and child outcomes, and had the important advantage of conceptual clarity.18 However, they cannot quantify the magnitude of different processes explaining the observed association. The CoS model used in this study provided a powerful quantitative approach to disentangle and quantify the underlying processes explaining the observed association, which had several advantages. First, the model used multiple relative groups, thus increasing analytical power and improving generalizability. Second, more than one child from each nuclear family can be included in the model. Therefore, it was possible to study family-level risk factors that influenced all children in the same family. Third, the model can quantify the degree to which the association between parental characteristics and child outcomes is consistent with a causal influence, or instead is due to confounding factors (environmental or genetic). The results in this study should also be considered in the context of its limitations. First, although recent validation checks of ADHD diagnoses in Swedish registers indicated low numbers of false-positives, our case identification strategy could not avoid false-negatives, especially for older children in this cohort. The potential misclassification should be non-differential for population-based comparison, and would lead to null findings; hence, our findings are probably conservative estimates of the actual
International Journal of Epidemiology, 2014, Vol. 0, No. 0
International Journal of Epidemiology, 2014, Vol. 0, No. 0
Conflict of interest: Dr H. Larsson has served as a speaker for Eli Lilly & Co., and his association with Eli Lilly was not related to this publication in any way. All other authors declared no conflicts of interest.
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