Since 1968, the Danish Civil Registration System has assigned a unique individual identifier to all residents of Denmark, which provides information on a person's date of birth as well as gender (20). The civil registration number is used as a personal identifier in all national registers, enabling accurate linkage.
The Danish Psychiatric Central Register was computerized in 1969 and currently includes data on approximately 725,000 persons and 3.25 million contacts, with virtually complete coverage of the entire population of Denmark (21). This register contains data on all admissions to Danish psychiatric inpatient facilities, and since 1995, registration of psychiatric outpatient services has been included. There are no private psychiatric inpatient facilities in Denmark, ensuring that all psychiatric admissions are represented in the register.
The Danish National Hospital Registry contains records for all inpatients treated in Danish nonpsychiatric hospitals since 1977, and since 1995, it has included outpatient and emergency room contacts (22).
From 1977 to 1993, diagnostic information in these psychiatric and hospital registers was based on the Danish modification of ICD-8 (23), and from 1994 to 2006, the diagnostic system was based on the Danish modification of ICD-10 (24). All treatments in Danish hospitals are free of charge for all residents.
All individuals born in Denmark between January 1, 1945, and December 31, 1996, and who were alive during the study period were included in our analyses. We conducted a cohort study that followed a total of 3,567,573 persons from the first day of 1977 until onset of the disorders of interest, death, emigration from Denmark, or the last day of 2006, whichever came first. During the study period (from 1977 to 2006), complete information on these individuals was available from the national registers. Information pertaining to autoimmune diseases and infections in individuals in this cohort was obtained from the Danish National Hospital Register. Cohort members were linked with the Danish Psychiatric Central Register and followed from their 10th birthday to establish whether they received a diagnosis of a schizophrenia spectrum disorder.
Persons with schizophrenia or schizophrenia-like psychoses (including schizotypal personality disorder [ICD-8: 295, 296.89, 297, 298.39, 301.83; ICD-10: F20–F29]), as diagnosed by the patient's treating psychiatrist, were included in the study. Date of illness onset was defined as the first day of the first hospital contact for a schizophrenia spectrum disorder, irrespective of other previous psychiatric diagnoses. Parental psychiatric history was identified from the Danish Psychiatric Central Register based on any psychiatric contact made by a patient's parents. Substance use disorders (ICD-8: 291, 294.30, 294.38, 303, 304; ICD-10: F10–F19) were identified from both the Danish Psychiatric Central Register and the Danish National Hospital Register.
The time of onset of an autoimmune disease or infection was defined as the first day of the first hospital contact for one of these diagnoses as recorded in the Danish National Hospital Register. Each person could have a history of more than one autoimmune disease and more than one infection. Individuals were classified as having a positive history of one or more autoimmune diseases, as shown in Table 1 (described in detail in the recent study by Eaton et al. ), if they had an in- or outpatient hospital contact for the relevant diagnosis. When defining infection, we omitted all ICD-8 diagnoses with the modification code “suspected” or “not found” and similar codes in ICD-10. Further, we omitted AIDS/HIV (07983, B20–24). An individual's first registered infection was categorized as follows: sepsis infection (ICD-8: 038, ICD-10: A40–A41), hepatitis infection (ICD-8: 070, ICD-10: B15–B19), gastrointestinal infection (ICD-8: 000–009, 540, ICD-10: A00–A09, K35), skin infection (ICD-8: 035, 050–057, 110–111, 680–686, ICD-10: B00–B09, A46, L00–L08), respiratory infection (ICD-8: 460–486, ICD-10: J00–J18), pregnancy-related infection (ICD-8: 630, 635, 670, ICD-10: 023, 0264, 085–086, 098), urogenital infection (ICD-8: 612, 620, 622, 590, 59500–59501, ICD-10: N300, N518B, N70–N72, N76, N770D, N771B, N771L), CNS infection (ICD-8: 013, 02701, 03609, 04000–04399, 045–046, 05201, 05302, 05403, 05501, 05601, 062–065, 07199, 07202, 07501, 07929, 09049, 0949, 320–324, 392, 47400, ICD-10: DA022C, DA066, DA17, DA229C, DA321, DA390, DA504, DA514B, DA521A–B, DA548A,D, DA80–DA89, DB003–DB004, DB010–DB011, DB020–DB021, DB050–DB051, DB060, DB261–DB262, DB375, DB451, DB582, DB602, DE236A, DG0, DI02, DP352A), or other type of infection (i.e., the remaining infections within the general chapters ICD-8: 000–136 and ICD-10: A, B; together with ICD-8: 710 and ICD-10: M00). Time since the most recent infection was established by examining individuals with a first, second, or third infection. The latter group could have three or more infections, but only the third infection was included in the time-dependent analyses because of practical considerations.
Data were analyzed using survival analysis. The relative risk of schizophrenia was estimated with a log linear Poisson regression model using the GENMOD procedure in SAS, version 9.2 (SAS Institute, Cary, N.C.). This method approximates a Cox regression. All analyses were adjusted for calendar year, age, and the interaction of age with sex. Age and calendar year and the occurrence of an infection, autoimmune disease, or substance use disorder as well as the psychiatric contacts among parents were treated as time-dependent variables (26), whereas all other variables were considered time independent. The p values and 95% confidence intervals (CIs) were based on likelihood ratio tests. Incidence rate ratio, which is the estimate of relative risk, was calculated using log-likelihood estimation. Synergy index was calculated using the method described by Andersson et al. (27). The population-attributable risk was estimated using methods described by Bruzzi et al. (28).