Different case definitions of schizophrenia have been used in register based research. However, no previous study has externally validated two different case definitions of schizophrenia against a wide range of risk factors for schizophrenia. We investigated hazard ratios (HRs) for a wide range of risk factors for ICD-10 DCR schizophrenia using a nationwide Danish sample of 2,772,144 residents born in 1955–1997. We compared one contact only (OCO) (the case definition of schizophrenia used in Danish register based studies) with two or more contacts (TMC) (a case definition of at least 2 inpatient contacts with schizophrenia). During the follow-up, the OCO definition included 15,074 and the TMC 7562 cases; i.e. half as many. The TMC case definition appeared to select for a worse illness course. A wide range of risk factors were uniformly associated with both case definitions and only slightly higher risk estimates were found for the TMC definition. Choosing at least 2 inpatient contacts with schizophrenia (TMC) instead of the currently used case definition would result in almost similar risk estimates for many well-established risk factors. However, this would also introduce selection and include considerably fewer cases and reduce power of e.g. genetic studies based on register-diagnosed cases only.
The decision on when to define a case of schizophrenia in register-based research is guided by several considerations. In Denmark, one contact to the secondary health care system with schizophrenia has been viewed as sufficient to define a case in register-based research. To increase the diagnostic validity, by minimizing false-positive diagnoses, researchers using the Swedish hospital discharge register sometimes employ a definition requiring a diagnosis of schizophrenia on two separate treatment inpatient contacts (Lichtenstein et al., 2006). However, a case definition of schizophrenia demanding two or more contacts (TMC) could lead to increased risk of selection. On the other hand, the advantage of the TMC definition is reduced heterogeneity among cases and a more homogeneous sample suited for e.g. biological studies (Fazel et al., 2009, Ripke et al., 2013, Ruderfer et al., 2014, Purcell et al., 2014, Rees et al., 2014 and Szatkiewicz et al., 2014). Conversely, the potential disadvantage of the OCO (one case only) definition used in Denmark is a higher risk of false-positive diagnoses. There has been several reports (Dalman et al., 2002, Ekholm et al., 2005 and Uggerby et al., 2013) suggesting that the validity of a schizophrenia diagnosis is good in Swedish as well as in Danish nationwide registers. However, since there are no supportive diagnostic tests for schizophrenia, it may be important, when designing e.g. future genetic studies based on register-based samples only, to consider when to use alternative ascertainment or not. In large register-based studies, sample size and effects of common and well-established risk factors could potentially depend on the case definition of schizophrenia. To study this further, we here examine the TMC definition versus the OCO definition in an external validation study. We decided to use well-established risk factors for schizophrenia as external validators as suggested previously (Robins and Guze, 1970). These included family history of mental illness (Mortensen et al., 1999), urban place of birth (Pedersen and Mortensen, 2001), unknown parent status (Mortensen et al., 1999), advanced paternal age (Sorensen et al., 2014 and McGrath et al., 2014), early parental loss (Sorensen et al., 2014), second generation immigration status (Sorensen et al., 2014), low birth weight (Abel et al., 2010), short gestational age (Byrne et al., 2007 and Nosarti et al., 2012), obstetric complications (Cannon et al., 2002), birth order (Kemppainen et al., 2001 and Pedersen and Mortensen, 2004), and Apgar score (Clarke et al., 2011).
