A generalisability theory approach to quantifying changes in psychopathology among ultra-high-risk individuals for psychosis.

Distinguishing stable and fluctuating psychopathological features in young individuals at Ultra High Risk (UHR) for psychosis is challenging, but critical for building robust, accurate, early clinical detection and prevention capabilities. Over a 24-month period, 159 UHR individuals were assessed using the Positive and Negative Symptom Scale (PANSS). Generalisability Theory was used to validate the PANSS with this population and to investigate stable and fluctuating features, by estimating the reliability and generalisability of three factor (Positive, Negative, and General) and five factor (Positive, Negative, Cognitive, Depression, and Hostility) symptom models. Acceptable reliability and generalisability of scores across occasions and sample population were demonstrated by the total PANSS scale (Gr = 0.85). Fluctuating symptoms (delusions, hallucinatory behaviour, lack of spontaneity, flow in conversation, emotional withdrawal, and somatic concern) showed high variability over time, with 50-68% of the variance explained by individual transient states. In contrast, more stable symptoms included excitement, poor rapport, anxiety, guilt feeling, uncooperativeness, and poor impulse control. The 3-factor model of PANSS and its subscales showed robust reliability and generalisability of their assessment scores across the UHR population and evaluation periods (G = 0.77-0.93), offering a suitable means to assess psychosis risk. Certain subscales within the 5-factor PANSS model showed comparatively lower reliability and generalisability (G = 0.33-0.66). The identified and investigated fluctuating symptoms in UHR individuals are more amendable by means of intervention, which could have significant implications for preventing and addressing psychosis. Prioritising the treatment of fluctuating symptoms could enhance intervention efficacy, offering a sharper focus in clinical trials. At the same time, using more reliable total scale and 3 subscales can contribute to more accurate assessment of enduring psychosis patterns in clinical and experimental settings.

Filter and Wrapper Stacking Ensemble (FWSE): a robust approach for reliable biomarker discovery in high-dimensional omics data.

Selecting informative features, such as accurate biomarkers for disease diagnosis, prognosis and response to treatment, is an essential task in the field of bioinformatics. Medical data often contain thousands of features and identifying potential biomarkers is challenging due to small number of samples in the data, method dependence and non-reproducibility. This paper proposes a novel ensemble feature selection method, named Filter and Wrapper Stacking Ensemble (FWSE), to identify reproducible biomarkers from high-dimensional omics data. In FWSE, filter feature selection methods are run on numerous subsets of the data to eliminate irrelevant features, and then wrapper feature selection methods are applied to rank the top features. The method was validated on four high-dimensional medical datasets related to mental illnesses and cancer. The results indicate that the features selected by FWSE are stable and statistically more significant than the ones obtained by existing methods while also demonstrating biological relevance. Furthermore, FWSE is a generic method, applicable to various high-dimensional datasets in the fields of machine intelligence and bioinformatics.

RNA-sequencing of peripheral whole blood of individuals at ultra-high-risk for psychosis - A longitudinal perspective.

BACKGROUND: The peripheral blood is an attractive source of prognostic biomarkers for psychosis conversion. There is limited research on the transcriptomic changes associated with psychosis conversion in the peripheral whole blood. STUDY DESIGN: We performed RNA-sequencing of peripheral whole blood from 65 ultra-high-risk (UHR) participants and 70 healthy control participants recruited in the Longitudinal Youth-at-Risk Study (LYRIKS) cohort. 13 UHR participants converted in the study duration. Samples were collected at 3 timepoints, at 12-months interval across a 2-year period. We examined whether the genes differential with psychosis conversion contain schizophrenia risk loci. We then examined the functional ontologies and GWAS associations of the differential genes. We also identified the overlap between differentially expressed genes across different comparisons. STUDY RESULTS: Genes containing schizophrenia risk loci were not differentially expressed in the peripheral whole blood in psychosis conversion. The differentially expressed genes in psychosis conversion are enriched for ontologies associated with cellular replication. The differentially expressed genes in psychosis conversion are associated with non-neurological GWAS phenotypes reported to be perturbed in schizophrenia and psychosis but not schizophrenia and psychosis phenotypes themselves. We found minimal overlap between the genes differential with psychosis conversion and the genes that are differential between pre-conversion and non-conversion samples. CONCLUSION: The associations between psychosis conversion and peripheral blood-based biomarkers are likely to be indirect. Further studies to elucidate the mechanism behind potential indirect associations are needed.

Investigation of social and cognitive predictors in non-transition ultra-high-risk' individuals for psychosis using spiking neural networks.

Finding predictors of social and cognitive impairment in non-transition Ultra-High-Risk individuals (UHR) is critical in prognosis and planning of potential personalised intervention strategies. Social and cognitive functioning observed in youth at UHR for psychosis may be protective against transition to clinically relevant illness. The current study used a computational method known as Spiking Neural Network (SNN) to identify the cognitive and social predictors of transitioning outcome. Participants (90 UHR, 81 Healthy Control (HC)) completed batteries of neuropsychological tests in the domains of verbal memory, working memory, processing speed, attention, executive function along with social skills-based performance at baseline and 4 × 6-month follow-up intervals. The UHR status was recorded as Remitters, Converters or Maintained. SNN were used to model interactions between variables across groups over time and classify UHR status. The performance of SNN was examined relative to other machine learning methods. Higher interaction between social and cognitive variables was seen for the Maintained, than Remitter subgroup. Findings identified the most important cognitive and social variables (particularly verbal memory, processing speed, attention, affect and interpersonal social functioning) that showed discriminative patterns in the SNN models of HC vs UHR subgroups, with accuracies up to 80%; outperforming other machine learning models (56-64% based on 18 months data). This finding is indicative of a promising direction for early detection of social and cognitive impairment in UHR individuals that may not anticipate transition to psychosis and implicate early initiated interventions to stem the impact of clinical symptoms of psychosis.

Constrained neuro fuzzy inference methodology for explainable personalised modelling with applications on gene expression data.

Interpretable machine learning models for gene expression datasets are important for understanding the decision-making process of a classifier and gaining insights on the underlying molecular processes of genetic conditions. Interpretable models can potentially support early diagnosis before full disease manifestation. This is particularly important yet, challenging for mental health. We hypothesise this is due to extreme heterogeneity issues which may be overcome and explained by personalised modelling techniques. Thus far, most machine learning methods applied to gene expression datasets, including deep neural networks, lack personalised interpretability. This paper proposes a new methodology named personalised constrained neuro fuzzy inference (PCNFI) for learning personalised rules from high dimensional datasets which are structurally and semantically interpretable. Case studies on two mental health related datasets (schizophrenia and bipolar disorders) have shown that the relatively short and simple personalised fuzzy rules provided enhanced interpretability as well as better classification performance compared to other commonly used machine learning methods. Performance test on a cancer dataset also showed that PCNFI matches previous benchmarks. Insights from our approach also indicated the importance of two genes (ATRX and TSPAN2) as possible biomarkers for early differentiation of ultra-high risk, bipolar and healthy individuals. These genes are linked to cognitive ability and impulsive behaviour. Our findings suggest a significant starting point for further research into the biological role of cognitive and impulsivity-related differences. With potential applications across bio-medical research, the proposed PCNFI method is promising for diagnosis, prognosis, and the design of personalised treatment plans for better outcomes in the future.