Robust data-driven identification of risk factors and their interactions: A simulation and a study of parental and demographic risk factors for schizophrenia.

David Gyllenberg,Andre Sourander,Alan S Brown,Ian W Mckeague

doi:10.1002/mpr.1834

Abstract

ObjectivesFew interactions between risk factors for schizophrenia have been replicated, but fitting all such interactions is difficult due to high‐dimensionality. Our aims are to examine significant main and interaction effects for schizophrenia and the performance of our approach using simulated data.MethodsWe apply the machine learning technique elastic net to a high‐dimensional logistic regression model to produce a sparse set of predictors, and then assess the significance of odds ratios (OR) with Bonferroni‐corrected p‐values and confidence intervals (CI). We introduce a simulation model that resembles a Finnish nested case–control study of schizophrenia which uses national registers to identify cases (n = 1,468) and controls (n = 2,975). The predictors include nine sociodemographic factors and all interactions (31 predictors).ResultsIn the simulation, interactions with OR = 3 and prevalence = 4% were identified with <5% false positive rate and ≥80% power. None of the studied interactions were significantly associated with schizophrenia, but main effects of parental psychosis (OR = 5.2, CI 2.9–9.7; p < .001), urbanicity (1.3, 1.1–1.7; p = .001), and paternal age ≥35 (1.3, 1.004–1.6; p = .04) were significant.ConclusionsWe have provided an analytic pipeline for data‐driven identification of main and interaction effects in case–control data. We identified highly replicated main effects for schizophrenia, but no interactions.

Highlights

Evidence suggests that schizophrenia is a disorder with a multifactorial etiology
Interactions reported in ≥2 papers and interaction in same direction Familial liability ✕ urbanicity Family history of psychoses ✕ urbanicitya Family history of schizophrenia-spectrum disorders ✕ urbanicityb Family history of any psychiatric hospitalization ✕ urbanicityb Familial liability ✕ maternal infection Parental psychosis ✕ prenatal effect of pyelonephritis (Clarke, Tanskanen, Huttunen, Whittaker, & Cannon, 2009)b Maternal psychiatric disorders ✕ maternal infection during pregnancy (Blomström et al, 2016)a Male sex ✕ maternal stress during pregnancy Male sex ✕ maternal stress during second trimesterb Male sex ✕ maternal daily stress during pregnancy (Fineberg et al, 2016)a
Interactions reported in ≥2 papers but interaction in opposite direction Familial liability ✕ paternal age Absent family history of schizophrenia ✕ advanced paternal age (Sipos et al, 2004)b Sister with schizophrenia-related diagnosis ✕ advanced paternal age (Perrin et al, 2010)a,c

Summary

Introduction

Evidence suggests that schizophrenia is a disorder with a multifactorial etiology. While individual environmental risk factors for schizophrenia have been identified (Radua et al, 2018), reviews have suggested that the disorder likely results from interactions between them and susceptibility genes (Cannon et al, 2003; van Os, Kenis, & Rutten, 2010). Interactions reported in ≥2 papers and interaction in same direction Familial liability ✕ urbanicity Family history of psychoses ✕ urbanicity (van Os, Hanssen, Bak, Bijl, & Vollebergh, 2003)a Family history of schizophrenia-spectrum disorders ✕ urbanicity (van Os, Pedersen, & Mortensen, 2004)b Family history of any psychiatric hospitalization ✕ urbanicity (van Os et al, 2004)b Familial liability ✕ maternal infection Parental psychosis ✕ prenatal effect of pyelonephritis (Clarke, Tanskanen, Huttunen, Whittaker, & Cannon, 2009)b Maternal psychiatric disorders ✕ maternal infection during pregnancy (Blomström et al, 2016)a Male sex ✕ maternal stress during pregnancy Male sex ✕ maternal stress during second trimester (van Os & Selten, 1998)b Male sex ✕ maternal daily stress during pregnancy (Fineberg et al, 2016)a. The literature search is described in detail in the Supporting Information. aThe outcome was schizophrenia-spectrum disorders or nonaffective psychoses. bThe outcome was schizophrenia. cThe finding was restricted to females. dThe study was restricted to males

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