O6.4. ASSOCIATION BETWEEN CLUSTERS OF FORMAL THOUGHT DISORDERS SEVERITY AND NEUROCOGNITIVE AND FUNCTIONAL OUTCOME INDICES IN THE EARLY STAGES OF PSYCHOSIS – RESULTS FROM THE PRONIA COHORT
Authors: Öztürk Ömer Faruk , Pigoni Alessandro , Wenzel Julian , Haas Shalaila , Popovic David , Ruef Anne , Dwyer Dominic B , Kambeitz-Ilankovic Lana , Haidl Theresa , Rosen Marlene , Kambeitz Joseph , Ruhrmann Stephan , Chisholm Katharine , Schultze-Lutter Frauke , Liddle Peter F , Upthegrove Rachel , Salokangas Raimo K R , Pantelis Christos , Meisenzahl Eva , Wood Stephen J , Brambilla Paolo , Borgwardt Stefan , Falkai Peter , Antonucci Linda A , Koutsouleris Nikolaos 
Published: May 2020

Abstract

Background
Formal thought disorder (FThD) has been associated with more severe illness courses and functional deficits in psychosis patients. Given these associations, it remains unclear whether the presence of FThD accounts for the heterogeneous presentation of psychoses, and whether it characterises a specific subgroup of patients showing prominent differential illness severity, neurocognitive and functional impairments already in the early stages of psychosis. Thus, our aim is 1) to evaluate whether there are stable subtypes of patients with Recent-Onset Psychosis (ROP) that are characterized by distinct FThD patterns, 2) to investigate whether this FThD-related stratification is associated with clinical, and neurocognitive phenotypes at an early stage of the disease, and 3) to explore correlation patterns among the FThD-related symptoms, functioning and neurocognition through network analysis.

Methods
279 individuals experiencing ROP were recruited for this project as part of multi-site European PRONIA study. In the present study, FThD was assessed with conceptual disorganization, difficulty in abstract thinking, poverty of content of speech, increased latency of response and poverty of speech items from the Positive and Negative Symptom Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). We first applied a multi-step clustering protocol comparing three clustering algorithms: (i) k-means, (ii) hierarchical clustering, and (iii) partitioning around medoids with the number of clusters ranging from 2 to 10. Our protocol runs following four checkpoints; (i) validity [ClValid package], (ii) re-evaluation of validity results and unbiased determination of the winning algorithm [NbClust package], (iii) stability test [ClusterStability package] and (iv) generalizability [predict.strength package] testing for the most optimal clustering solution. Thereafter, we investigated whether the identified FThD subgrouping solution was associated with neurocognitive performance, social and occupational functioning by using Welch’s two-sample t-test or Mann-Whitney-U test based on the distribution of data, and explored the interrelation of these domains with network analysis by using qgraph package with the spearman correlation matrix among variables. All analyses and univariate statistical comparisons were conducted with R version 3.5.2. We used the False Discovery Rate (FDR)37 to correct all P-values for the multiple comparisons.

Results
The k-means algorithm-based on two-cluster solution (FThD high vs. low) surviving these validity, stability and generalizability tests was chosen for further association tests and network analysis with core disease phenotypes. Patients in FThD high subgroup had lower scores in global (pfdr = 0.0001), social (pfdr &lt; 0.0001) and role (pfdr &lt; 0.0001) functioning, in semantic (pfdr &lt; 0.0001) and phonological verbal fluency (pfdr = 0.0004), verbal short-term memory (pfdr = 0.0018) and abstract thinking (pfdr = 0.0099). Cluster assignment was not informed by the global disease severity (pfdr = 0.7786) but was associated with more pronounced negative symptoms (pfdr = 0.0001) in the FThD high subgroup.

Discussion
Our findings highlight how the combination of unsupervised machine learning algorithms with network analysis techniques may provide novel insight about the mappings between psychopathology, neurocognition and functioning. Furthermore, they point how FThD may represent a target variable for individualized psycho-, socio-, logotherapeutic interventions aimed at improving neurocognition abilities and functioning. Prospective studies should further test this promising perspective.