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

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.

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“…Recently, we built a new reliable and replicable, data-driven model of schizophrenia, namely a nomothetic network, which reflects the effects of risk and resilience factors and adverse outcome pathways (AOPs) on the cognitome, symptomatome and phenomenome of schizophrenia [1]. The symptomatome of schizophrenia can best be conceptualized as a latent vector, extracted from various symptom domain scores, namely psychosis, hostility, excitation, and mannerism (PHEM), negative symptoms, psychomotor retardation (PMR), and formal thought disorders (FTD) [1][2][3]. All these symptom domains are manifestations of a single underlying trait, namely overall severity of symptoms of schizophrenia (OSOS), which determines to a large extent its symptomatic manifestations [1][2][3].…”

“…The cognitome (defined as the aggregate of cognitive dysfunctions) of schizophrenia can best be conceptualized as a latent vector extracted from different neurocognitive dysfunctions including impairments in recall, semantic and episodic memory, strategy use, executive functions, visual sustained attention, attention set-shifting, rule acquisition, and emotional recognition [1,[4][5][6][7]. This latent vector was computed using various probes of a) the Cambridge Neuropsychological Test Automated Battery [8], and b) the Consortium to Establish a Registry for Alzheimer's disease [1,9,10]. Impairments in those neurocognitive probes are manifestations of a single underlying trait, namely a Generalized Cognitive Decline (G-CoDe), which determines to a large extent all its cognitive manifestations [1].…”

“…This latent vector was computed using various probes of a) the Cambridge Neuropsychological Test Automated Battery [8], and b) the Consortium to Establish a Registry for Alzheimer's disease [1,9,10]. Impairments in those neurocognitive probes are manifestations of a single underlying trait, namely a Generalized Cognitive Decline (G-CoDe), which determines to a large extent all its cognitive manifestations [1].…”

“…Both OSOS and G-CoDe are strongly associated with the phenomenome of schizophrenia (defined as the self-description of illness features by the patient) as assessed using the self-rated World Health Organization Quality of Life Instrument-Abbreviated version (WHO-QoL-BREF) [11]. The latter assesses physical health, psychological health, and social and environmental responsible behaviors [1]. We found that G-CoDe and OSOS explain 40.9% of the variance in a LV extracted from those 4 WHO-QoL-BREF domains, reflecting an overall decline in HR-QoL (OD-QoL) [1,5].…”

“…The latter assesses physical health, psychological health, and social and environmental responsible behaviors [1]. We found that G-CoDe and OSOS explain 40.9% of the variance in a LV extracted from those 4 WHO-QoL-BREF domains, reflecting an overall decline in HR-QoL (OD-QoL) [1,5]. Nevertheless, there are no data whether there are differences in G-CoDe, OSOS, and OD-Qol between patients with first episode schizophrenia (FES) and those with multiple episode schizophrenia (MES).…”