Deep Clinical Phenotyping of Schizophrenia Spectrum Disorders Using Data-Driven Methods: Marching towards Precision Psychiatry.

Heterogeneity is the main challenge in the traditional classification of mental disorders, including schizophrenia spectrum disorders (SSD). This can be partly attributed to the absence of objective diagnostic criteria and the multidimensional nature of symptoms and their associated factors. This article provides an overview of findings from the Genetic Risk and Outcome of Psychosis (GROUP) cohort study on the deep clinical phenotyping of schizophrenia spectrum disorders targeting positive and negative symptoms, cognitive impairments and psychosocial functioning. Three to four latent subtypes of positive and negative symptoms were identified in patients, siblings and controls, whereas four to six latent cognitive subtypes were identified. Five latent subtypes of psychosocial function-multidimensional social inclusion and premorbid adjustment-were also identified in patients. We discovered that the identified subtypes had mixed profiles and exhibited stable, deteriorating, relapsing and ameliorating longitudinal courses over time. Baseline positive and negative symptoms, premorbid adjustment, psychotic-like experiences, health-related quality of life and PRSSCZ were found to be the strong predictors of the identified subtypes. Our findings are comprehensive, novel and of clinical interest for precisely identifying high-risk population groups, patients with good or poor disease prognosis and the selection of optimal intervention, ultimately fostering precision psychiatry by tackling diagnostic and treatment selection challenges pertaining to heterogeneity.

Multivariate Density Estimation by Neural Networks.

We propose nonparametric methods to obtain the Probability Density Function (PDF) to assess the properties of the underlying data generating process (DGP) without imposing any assumptions on the DGP, using neural networks (NNs). The proposed NN has advantages compared to well-known parametric and nonparametric density estimators. Our approach builds on literature on cumulative distribution function (CDF) estimation using NN. We extend this literature by providing analytical derivatives of this obtained CDF. Our approach hence removes the numerical approximation error in differentiating the CDF output, leading to more accurate PDF estimates. The proposed solution applies to any NN model, i.e., for any number of hidden layers or hidden neurons in the multilayer perceptron (MLP) structure. The proposed solution applies the PDF estimation by NN to continuous distributions as well as discrete distributions. We also show that the proposed solution to obtain the PDF leads to good approximations when applied to correlated variables in a multivariate setting. We test the performance of our method in a large Monte Carlo simulation using various complex distributions. Subsequently, we apply our method to estimate the density of the number of vehicle counts per minute measured with road sensors for a time window of 24 h.

Multivariate Count Data Models for Time Series Forecasting.

Count data appears in many research fields and exhibits certain features that make modeling difficult. Most popular approaches to modeling count data can be classified into observation and parameter-driven models. In this paper, we review two models from these classes: the log-linear multivariate conditional intensity model (also referred to as an integer-valued generalized autoregressive conditional heteroskedastic model) and the non-linear state-space model for count data. We compare these models in terms of forecasting performance on simulated data and two real datasets. In simulations, we consider the case of model misspecification. We find that both models have advantages in different situations, and we discuss the pros and cons of inference for both models in detail.

Genome-wide analysis of macrosatellite repeat copy number variation in worldwide populations: evidence for differences and commonalities in size distributions and size restrictions.

BACKGROUND: Macrosatellite repeats (MSRs), usually spanning hundreds of kilobases of genomic DNA, comprise a significant proportion of the human genome. Because of their highly polymorphic nature, MSRs represent an extreme example of copy number variation, but their structure and function is largely understudied. Here, we describe a detailed study of six autosomal and two X chromosomal MSRs among 270 HapMap individuals from Central Europe, Asia and Africa. Copy number variation, stability and genetic heterogeneity of the autosomal macrosatellite repeats RS447 (chromosome 4p), MSR5p (5p), FLJ40296 (13q), RNU2 (17q) and D4Z4 (4q and 10q) and X chromosomal DXZ4 and CT47 were investigated. RESULTS: Repeat array size distribution analysis shows that all of these MSRs are highly polymorphic with the most genetic variation among Africans and the least among Asians. A mitotic mutation rate of 0.4-2.2% was observed, exceeding meiotic mutation rates and possibly explaining the large size variability found for these MSRs. By means of a novel Bayesian approach, statistical support for a distinct multimodal rather than a uniform allele size distribution was detected in seven out of eight MSRs, with evidence for equidistant intervals between the modes. CONCLUSIONS: The multimodal distributions with evidence for equidistant intervals, in combination with the observation of MSR-specific constraints on minimum array size, suggest that MSRs are limited in their configurations and that deviations thereof may cause disease, as is the case for facioscapulohumeral muscular dystrophy. However, at present we cannot exclude that there are mechanistic constraints for MSRs that are not directly disease-related. This study represents the first comprehensive study of MSRs in different human populations by applying novel statistical methods and identifies commonalities and differences in their organization and function in the human genome.