How to Construct a Bottom-Up Nomothetic Network Model and Disclose Novel Nosological Classes by Integrating Risk Resilience and Adverse Outcome Pathways with the Phenome of Schizophrenia.

Michael Maes,Aristo Vojdani,Buranee Kanchanatawan,Piotr Galecki

doi:10.3390/brainsci10090645

Abstract

Current case definitions of schizophrenia (DSM-5, ICD), made through a consensus among experts, are not cross-validated and lack construct reliability validity. The aim of this paper is to explain how to use bottom-up pattern recognition approaches to construct a reliable and replicable nomothetic network reflecting the direct effects of risk resilience (RR) factors, and direct and mediated effects of both RR and adverse outcome pathways (AOPs) on the schizophrenia phenome. This study was conducted using data from 40 healthy controls and 80 patients with schizophrenia. Using partial least squares (PLS) analysis, we found that 39.7% of the variance in the phenomenome (lowered self-reported quality of life) was explained by the unified effects of AOPs (IgA to tryptophan catabolites, LPS, and the paracellular pathway, cytokines, and oxidative stress biomarkers), the cognitome (memory and executive deficits), and symptomatome (negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, formal thought disorders); 55.8% of the variance in the symptomatome was explained by a single trait extracted from AOPs and the cognitome; and 22.0% of the variance in the latter was explained by the RR (Q192R polymorphism and CMPAase activity, natural IgM, and IgM levels to zonulin). There were significant total effects (direct + mediated) of RR and AOPs on the symptomatome and the phenomenome. In the current study, we built a reliable nomothetic network that reflects the associations between RR, AOPs, and the phenome of schizophrenia and discovered new diagnostic subclasses of schizophrenia based on unified RR, AOPs, and phenome scores.

Highlights

We showed that the symptomatome of schizophrenia comprises psychosis, hostility, excitation, mannerism (PHEM), negative symptoms, formal thought disorders (FTD), and psychomotor retardation (PMR) and that these symptom domains are reflective manifestations of a single underlying trait, namely overall severity of schizophrenia (OSOS) [1,2]
The phenome consists of different components, whereby the causome may induce a strain on the internal environmentome, which may develop into neurotoxic adverse outcome pathways (AOPs)
This bottom-up model of schizophrenia was phenomenology. This bottom-up model of built based on inductive and causal reasoning through identification of the risk resilience (RR), AOPs, and phenome schizophrenia was built based on inductive and causal reasoning through identification of the RR, AOPs, and phenome and ensembling data drawn from those observations into a unified causal model. This contrasts with the current gold standard use of case definitions of schizophrenia proposed by the APA (DSM-5) and the WHO (ICD)

Summary

Introduction

We showed that the symptomatome of schizophrenia comprises psychosis, hostility, excitation, mannerism (PHEM), negative symptoms, formal thought disorders (FTD), and psychomotor retardation (PMR) and that these symptom domains are reflective manifestations of a single underlying trait, namely overall severity of schizophrenia (OSOS) [1,2]. The impairments in these cognitive domains are reflective manifestations of an overall deficit in cognitive functioning, reflecting impairments in prefronto-temporal, prefronto-parietal, prefronto-striato-thalamic, and hippocampal and amygdalal neural circuits [1,3,5,6,7]. These impairments in the “cognitome” (the aggregate of cognitive dysfunctions) are strongly related with the symptomatome of schizophrenia and, based on the available knowledge, we concluded that these cognitome impairments may play a role in the development and maintenance of the symptomatome [1,5]. Lowered HR-QoL in schizophrenia is strongly predicted by the symptomatome and impairments in the cognitome and is more pronounced in deficit schizophrenia than in non-deficit schizophrenia [3,8]

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