From the National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.
Received for publication October 24, 2003; accepted for publication April 6, 2004.
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ABSTRACT |
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birth intervals; birth order; confounding factors (epidemiology); only child; risk factors; schizophrenia; siblings; urbanization
Abbreviations: Abbreviation: ICD-8, International Classification of Diseases, Eighth Revision; ICD-10, The ICD-10 Classification of Mental and Behavioural Disorders.
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INTRODUCTION |
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It is very unlikely that sibship characteristics themselves would influence the risk of schizophrenia, suggesting that sibship characteristics are proxies for some unknown underlying cause(s) or exposure(s) responsible for the association between sibship characteristics and schizophrenia risk. Authors have used the birth order and birth interval to older siblings as proxy variables for prenatal exposure to infections (1, 3, 4), sibship size as a proxy variable for infections in childhood (1, 7), and a short birth interval to older siblings as a proxy variable for maternal folate depletion during pregnancy (6), while other authors studied the effect of sibship characteristics without reference to any specific hypothesis (2, 5).
Danish data suggest that sibship size increases with decreasing degree of urbanization but also that frequent change of residence, increasing degree of urbanization during upbringing (8), and increasing sibship size (1) increase schizophrenia risk. Therefore, one objective of this study is to explore the potential association between sibship characteristics and schizophrenia, while evaluating the potential confounding effect of change of residence and urbanization.
Sibship characteristics vary during upbringing for most children, meaning that, for example, an association between sibship size at the fifth birthday and schizophrenia may differ from that between sibship size at the 10th birthday and schizophrenia. Therefore, in addition to the associations explored in previous studies, we evaluate the potential association between sibship characteristics at various time points during upbringing and the risk of schizophrenia.
Detailed information on the timing of exposure in relation to sibship characteristics combined with appropriate adjustment for confounders may provide valuable information on the unknown underlying cause(s) or exposure(s) responsible for the association between sibship characteristics and schizophrenia.
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MATERIALS AND METHODS |
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Assessment of schizophrenia and mental illness in a parent or sibling
The study population and their mothers, fathers, and siblings were linked with the Danish Psychiatric Central Register (11), which has been computerized since April 1, 1969. The Danish Psychiatric Central Register contains data on all admissions to Danish psychiatric inpatient facilities and at present includes data on approximately 450,000 persons and 1.6 million admissions. From 1995 onward, information on outpatient visits to psychiatric departments was included in the register. From April 1969 to December 1993, the diagnostic system used was the Danish modification of the International Classification of Diseases, Eighth Revision (ICD-8) (12), and from January 1994 the diagnostic system used was The ICD-10 Classification of Mental and Behavioural Disorders (ICD-10) (13). Cohort members were classified with schizophrenia if they had been admitted to a psychiatric hospital or had been in outpatient care with a diagnosis of the disorder (ICD-8 code 295 or ICD-10 code F20). The date of onset was defined as the first day of the first contact (in- or outpatient) with a diagnosis of schizophrenia. Parents and siblings were categorized hierarchically with a history of schizophrenia, schizophrenia-like psychoses (ICD-8 codes 297, 298.39, and 301.83 or ICD-10 codes F21F29), or other mental disorders (any ICD-8 or ICD-10 diagnosis), respectively, if they had been admitted to a psychiatric hospital or had been in outpatient care with one of these diagnoses. The diagnostic categories used were identical to those used in previous studies (6, 8, 14).
Assessment of sibship composition
Using the person-identifiable information on all cohort members and their siblings, we calculated the following information: 1) the number of siblings 0 year, 1 year, 2 years, ..., 13 years, and 14 or more years older than the individual as 15 numerical variables; 2) the number of siblings 0 year, 1 year, 2 years, ..., 13 years, and 14 years younger than the individual as 15 numerical variables; 3) the number of children in the same birth (twinning); and 4) the age when getting half siblings for the first time ever.
By "siblings" we refer to children born to the same mother, and by "half siblings" we refer to siblings having different fathers. The number of older siblings was evaluated as the number of older siblings alive at the time of the individuals birth, and the number of younger siblings was evaluated at the time of younger siblings birth. By "0 years" we refer to the age level from birth to the first birthday, by "1 year" we refer to the age level from the first to the second birthday, and so on. By "sibship composition" we refer to the variables defined above. The method used on the ages of older siblings is almost identical to that used by Sham et al. (4), except that we used the number of older siblings in fifteen 1-year age levels while Sham et al. (4) used the number of older siblings in eight 1-year age levels.
Assessment of sibship size
We calculated the sibship size by age levels of the number of siblings who were alive at the childs birth, fifth birthday, 10th birthday, and 15th birthday. Note that, except for twins, sibship size at birth is identical to birth order, as both indicate the number of older siblings. Sibship size was categorized as one, two, three, four, and greater than or equal to five.
Assessment of change of residence and of urbanization at birth and during upbringing
Municipalities in Denmark were classified according to the degree of urbanization (15): capital, capital suburb, provincial city with more than 100,000 inhabitants, provincial town with more than 10,000 inhabitants, or rural areas. For each person in the cohort, we compiled information on the degree of urbanization at the place of birth; the accumulated number of years each person had been living in each degree of urbanization from birth to the 15th birthday; and the number of changes of municipality at the following age levels: 03, 49, 1012, and 1314 years. These variables were identical to those used in a previous study on urbanicity during upbringing and schizophrenia risk (8).
Study design
A total of 763,000 persons in 496,000 sibships (defined by the identity of the mothers) were followed from their 15th birthday or January 1, 1986, whichever came later, until the date of onset of schizophrenia, the date of death, the date of emigration from Denmark, or December 31, 2001, whichever came first. Note that all information recorded on cohort members is independent of the disease status, and that all cohort members have complete information on all variables, except for the 0.6 percent of cohort members with a missing paternal link.
Statistical analyses
The relative risk of schizophrenia was estimated by log-linear Poisson regression (16) with the GENMOD procedure in SAS version 8.2 software (17). All relative risks were adjusted for age and its interaction with gender, calendar year, parental age, history of mental illness in a parent or sibling, and the degree of urbanization at the place of birth. This model includes 45 parameters. Age, calendar year, and history of mental illness in siblings were treated as time-dependent variables (18), whereas all other variables were treated as variables independent of time. To reduce the risk of residual confounding, age was categorized as 15, 16, 17, 18, 19, 2021, 2223, 2425, 2627, and 2829 completed years; calendar year was categorized as 19861989, 19901992, 1993, 1994, 1995, 1996, 1997, 1998, 1999, 2000, and 2001 completed years; maternal age was categorized as 1217, 1819, 2021, 2224, 2529, 3034, 3539, and 40 completed years; and paternal age was categorized as 1217, 1819, 2021, 2224, 2529, 3034, 3539, 4044, 4549, and
50 completed years or unknown father. p values were based on likelihood ratio tests, and 95 percent confidence intervals were calculated by the Wald test (18). The adjusted-score test (19) suggested that the regression models were not subject to overdispersion.
Simplification of model
We used backward elimination (20) to reduce the number of parameters in the models describing the number of younger siblings at each of the 15 age levels (15 parameters) and the number of older siblings at each of the 15 age levels (15 parameters). At first, we fitted the full model with all variables (e.g., the number of siblings at 0 year, 1 year, 2 years, ..., 13 years, and 14 years younger than the individual) and used the Wald test (18) to evaluate the hypothesis that the parameter estimates associated with two successive age levels were equal (e.g., the risk associated with the number of siblings 1 year younger than the individual equals the risk associated with the number of siblings 2 years younger than the individual). The successive age levels whose parameter estimates were associated with the lowest significance level were collapsed into one variable (e.g., the number of siblings 12 years younger than the individual). This procedure was repeated until all successive parameters differed at a significance level of 0.05. This method is independent of prior assumptions about the association between sibship composition and schizophrenia. This simplification was performed separately for the number of younger siblings and the number of older siblings.
Population attributable risk
We calculated the population attributable risk as the fraction of the total number of cases of schizophrenia in the population that would not have occurred if the effect of a specific risk factor or factors had been eliminated (21).
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RESULTS |
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Overall, the crude incidence of schizophrenia in this cohort was 3.36 per 10,000 person-years at risk. For children who were only children (i.e., sibship size of one) at the 15th birthday, it was 4.57; for twins, 3.69; for children with half siblings at birth, 5.43; for children with a sibling 1 year younger, 3.68; and for children with a sibling 1 year older, it was 4.25 per 10,000 person-years at risk.
Sibship size
Sibship size at birth and at the fifth birthday had no significant effect on schizophrenia risk, while sibship size at the 10th and at the 15th birthdays had significant effects on schizophrenia risk (first adjustment) (table 1). Children with one sibling (i.e., sibship size of two) were chosen as the reference category. The effect of sibship size at the 10th and at the 15th birthdays was almost identical, with evidence of an elevated risk among only children and among children with a sibship size of four or more. When additional adjustment was made for change of residence and urbanization during upbringing (second adjustment) (table 1), the effect of sibship size at all ages was reduced; that is, the effect of sibship size is confounded by change of residence and urbanization during upbringing. Conversely, the effect of change of residence and urbanization during upbringing was not confounded by sibship size at any age (results not shown). With this adjustment, sibship size had no significant effect, but there was still some indication of an increased risk among only children and among children with a sibship size of four or more at the 10th and at the 15th birthdays.
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Younger siblings
The relative risk of schizophrenia depends on the birth interval to younger siblings (first adjustment) (table 3). Using backward elimination, we simplified this model with 15 parameters to a model with four parameters: siblings who were 06, 78, 910, and 1114 years younger (first adjustment, simplified model) (table 3). Siblings 06 and 910 years younger had no significant impact on schizophrenia risk, while siblings 78 and 1114 years younger increased risk significantly compared with children who had no younger siblings at these birth intervals.
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Interpretation of models
Estimates presented in the first adjustment in tables 2, 3, and 4 originate from one multivariate model; estimates presented in the first adjustment, simplified model, in tables 3 and 4 originate from a second multivariate model; and estimates presented in the second adjustment in tables 2, 3, and 4 originate from a third multivariate model. All sibship composition variables (sibship size excluded) were adjusted mutually. However, mutual adjustment had only a minor effect on the estimates presented.
The implication of the model describing the sibship composition is that children with one sibling have the risk described in tables 3 and 4, depending on the birth interval to that sibling, in comparison with children who had no siblings at the 15th birthday. For children with two siblings, the risks in the categories representing the appropriate birth intervals should be multiplied to obtain the risk of schizophrenia. For example, children with a sibling 5 years younger and a sibling 5 years older have a risk of 0.87 (calculated by 0.95 x 0.92) compared with children who had no siblings at the 15th birthday. By "siblings at the 15th birthday," we refer to children who had siblings who were alive at least 1 day from the individuals birth to the individuals 15th birthday.
Population attributable risk
If the risk for children with half siblings could be reduced to the risk for children without, 3.6 percent of the cases of schizophrenia would not have occurred. If the risk for all children could be reduced to the risk for children with one sibling with a birth interval of 26 years (older or younger sibling), 2.5 percent of the cases of schizophrenia would not have occurred.
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DISCUSSION |
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Sibship composition
The birth intervals to younger and older siblings and having half siblings affect the risk of schizophrenia significantly, while having a co-twin had no significant impact on schizophrenia risk. Therefore, our study demonstrated that both current sibship size and past history of changes in sibship composition influence schizophrenia risk significantly. For example, based on table 1, people with identical sibship sizes at the 15th birthday have identical risks. However, people may have obtained their sibship size in many different ways. Among those with one sibling at the 15th birthday, some are only children from 0 to 7 years and get a younger sibling at age 8 years, while others at birth have an older sibling aged 8 years. According to our model, these children have risks of 1.30 (95 percent confidence interval: 1.14, 1.49) and 0.92 (95 percent confidence interval: 0.86, 0.98), respectively.
The relative risks associated with the birth interval to younger siblings differ from the risks associated with the birth interval to older siblings (compare tables 3 and 4). This finding indicates that these effects cannot be explained by common factors in mothers. If a common factor in mothers could explain these effects, tables 3 and 4 would show identical effects by birth interval. For example, for a mother having two children with an age difference of 8 years, the younger child has a risk of 0.92, while the older child has a risk of 1.30. However, common factors in mothers may explain the nearly identical effect of intervals to younger and older siblings from 2 to 6 years and again from 9 to 11 years (tables 3 and 4).
Our results may support the hypotheses post factum that maternal folate depletion due to short birth interval to older siblings may increase schizophrenia risk, and that stress of getting younger siblings during puberty may increase schizophrenia risk. Furthermore, if divorces are more common in parents with a history of mental illness, the increased risk associated with a history of half siblings may be explained by undiagnosed mental illness in the parents of these children. However, other explanations may apply.
Comparison with previous studies
In previous studies on Danish data (1, 6), the authors found that sibship size and birth interval between siblings influence schizophrenia risk and that birth order had no influence on schizophrenia risk. In these studies, sibship size was measured as a time-varying variable that described the number of siblings from entry into the study (fifth birthday and 15th birthday, respectively) until censoring (end of study), estimating its effect using Poisson regression adjusting for age. As the incidence of schizophrenia for persons until the 15th birthday is very low and most siblings in Denmark are born with a birth interval of less than 15 years, this measure of sibship size corresponds approximately to measuring sibship size at the 15th birthday. We performed additional analyses in which we analyzed our data in exactly the same way as Westergaard et al. (1) and Smits et al. (6) had done. We found a similar association among schizophrenia risk, birth order, sibship size, and birth interval between siblings, except that a short birth interval to younger siblings had no effect in the current cohort, and we found a slightly lower effect of sibship size. The lack of association between a short birth interval to younger siblings and schizophrenia risk, which is also evident in table 3, and the lower impact of sibship size indicate that these associations may be more specific to late-onset cases of schizophrenia, as these studies include people with onset up to age 50 years, whereas our study includes only people with onset up to age 30 years.
Our study method on older siblings is almost equivalent to that used by Sham et al. (4), except that we used the birth interval to older siblings in fifteen 1-year age categories while Sham et al. (4) used the birth interval to older siblings in eight 1-year categories. Despite these similarities, Sham et al. (4) found an increased risk in children with siblings 34 years older, and we found a slightly protective, but significant effect of older siblings associated with these birth intervals.
Strengths and limitations
Our study demonstrated a significantly increased risk associated with siblings 78 and 1114 years younger combined with a significantly decreased risk associated with siblings 210 and 12 or more years older. Although these effects appear significant, we found no consistent pattern between the birth intervals of younger and older siblings and the risk of schizophrenia.
The results of the study are based on patients with schizophrenia admitted to a psychiatric hospital or in outpatient care with a diagnosis of schizophrenia. Although not all cases of schizophrenia are admitted or in outpatient care during the first episode, many of these will eventually be admitted or receive outpatient care and thus subsequently become registered. Our results may apply only to early-onset schizophrenia, since we restricted our cohort members to a birth year of 1971 or later. This restriction was necessary to adjust for change of residence and urbanization during upbringing, as this information is accessible only for cohort members born in 1971 or later. Another potential weakness of our study is that we did not adjust for the potential impact of dependence between cohort members in families. Such adjustment is not feasible due to computational issues.
The strength of this study is the very large sample containing all children born in Denmark to Danish women. Furthermore, data were analyzed as a cohort study using the total population as the comparison group, which prevents bias from arising through inappropriate control groups.
Conflicting results between studies
Even if studies from different countries used identical measures of a proxy variable (e.g., sibship size) for the underlying risk factor and if the underlying risk factor had an identical effect, the association between the proxy measured and schizophrenia risk will differ between countries if the association between the proxy measured and the underlying risk factor differs. This may be the case if the sibship characteristics of these countries differ (e.g., if the underlying risk factor was maternal folate depletion during pregnancy and if we evaluate the effect of the proxy variable sibship size at the 15th birthday; if the average birth interval between siblings is smaller in Denmark than in the country for comparison, children from large sibships in Denmark would suffer more from maternal folate depletion compared with children in the other country. Results from Denmark would therefore find a greater effect of large sibship size compared with those from the other country). Conclusively, results on the association between sibship characteristics from a single country and schizophrenia may not be comparable with results from other countries. This observation may explain some of the conflicting results between studies, although differences in the methods used may also explain some differences.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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