Age at onset mixture analysis and systematic comparison in schizophrenia spectrum disorders: Is the onset heterogeneity dependent on heterogeneous diagnosis?
Introduction
Among the numerous clinical features of schizophrenia spectrum disorders, age at onset (AAO) is widely recognized as a significant clinical and prognostic factor (Leung and Chue, 2000, Öngür et al., 2009).
Males with schizophrenia have consistently earlier onset, (Leung and Psych, 2000) and other factors such as winter birth (Davies et al., 2003, Torrey et al., 1997), alcohol/drug use (Hambrecht and Häfner, 1996, Dixon, 1999, Chambers et al., 2001), positive family history (Byrne et al., 2002, Mortensen et al., 1999) and ethnicity (Cantor-Graae and Selten, 2005) have also been associated with developing early onset schizophrenia.
Moreover, AAO has been proposed to be the single most important clue to understanding disease etiology (DeLisi, 1992, Tsuang, 2000). There is a growing body of literature demonstrating the clinical interest in early-onset schizophrenia (DeLisi, 1992, Leung and Chue, 2000, Aleman et al., 2003). However, the majority of age cut-off values for early and late onset are arbitrarily chosen and varied across studies (Schürhoff et al., 2004, Köhler et al., 2009, Panariello et al., 2010, De Luca et al., 2012, Vinokur et al., 2014). Therefore, it is expected that there will be significant differences when comparing the AAO distributions across different studies.
In this study, our aim was to obtain empirically derived subgroups of AAO using the admixture analysis. We investigated the effect of ethnicity and winter birth on the AAO in schizophrenia. Based on specific selection criteria, we also provide a review of the studies that have identified sub groups of AAO in schizophrenia. Furthermore, the cut-offs from the reviewed studies were applied to our sample in order to compare the distributions.
Section snippets
Study sample
A cross-sectional study of 612 unrelated patients was conducted. Patients were recruited for participation through the Centre for Addiction and Mental Health in Toronto as part of a study examining the genetics of schizophrenia. The study subjects were referred through the Schizophrenia Clinics at CAMH that assess patients with psychosis of age between 16 and 75. The patients were recruited by two Clinician-Scientists (JLK and VDL) from 1995 to 2012. To meet the criteria for inclusion patients
Demographics
We included 612 participants in our study. The mean age at assessment was 39.8 ± 11.83. There were 427 males and 185 females, 69.2% of the participants were from white Caucasian background and 30.8% were from mixed backgrounds (Table 1). The mean age at assessment was 39.82 ± 11.82 and the mean AAO was 22.125 ± 6.39.
Mclust analysis
The admixture analysis yielded a best fitting model of three Gaussian distributions with unequal variance describing the early, intermediate and late onset groups (Fig. 1). The early
Discussion
The purpose of our study was to assess whether schizophrenia segregates into clinically distinct sub-groups defined by the AAO. This study shows that the observed distribution of AAO in patients with schizophrenia is a combination of three normal distributions, with cutoffs at 19 and 27, identifying these subgroups.
There are several strengths in our study over the previous investigations. Firstly, our sample is the largest one that has been analyzed using the admixture analysis. Secondly, the
Role of funding source
No operating funds were granted to carry on this project.
Contributors
Dr Nowrouzi wrote the paper.
Roy Kahmi contributed to the analysis and manuscript writing.
Jayi Hu performed the literature review.
Michelle Matmari helped in the manuscript preparation.
Dr Kennedy is a clinical collaborator.
Dr De Luca is the senior author who designed the study.
Conflict of interest
Authors have no conflict.
Acknowledgment
Dr De Luca received a CIHR New Investigator Award.
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These two authors contributed equally to this work.