Variable levels of drift in tunicate cardiopharyngeal gene regulatory elements.

Background: Mutations in gene regulatory networks often lead to genetic divergence without impacting gene expression or developmental patterning. The rules governing this process of developmental systems drift, including the variable impact of selective constraints on different nodes in a gene regulatory network, remain poorly delineated. Results: Here we examine developmental systems drift within the cardiopharyngeal gene regulatory networks of two tunicate species, Corella inflata and Ciona robusta. Cross-species analysis of regulatory elements suggests that trans-regulatory architecture is largely conserved between these highly divergent species. In contrast, cis-regulatory elements within this network exhibit distinct levels of conservation. In particular, while most of the regulatory elements we analyzed showed extensive rearrangements of functional binding sites, the enhancer for the cardiopharyngeal transcription factor FoxF is remarkably well-conserved. Even minor alterations in spacing between binding sites lead to loss of FoxF enhancer function, suggesting that bound trans-factors form position-dependent complexes. Conclusions: Our findings reveal heterogeneous levels of divergence across cardiopharyngeal cis-regulatory elements. These distinct levels of divergence presumably reflect constraints that are not clearly associated with gene function or position within the regulatory network. Thus, levels of cis-regulatory divergence or drift appear to be governed by distinct structural constraints that will be difficult to predict based on network architectur

Traces of trauma – a multivariate pattern analysis of childhood trauma, brain structure and clinical phenotypes

Background: Childhood trauma (CT) is a major yet elusive psychiatric risk factor, whose multidimensional conceptualization and heterogeneous effects on brain morphology might demand advanced mathematical modeling. Therefore, we present an unsupervised machine learning approach to characterize the clinical and neuroanatomical complexity of CT in a larger, transdiagnostic context. Methods: We used a multicenter European cohort of 1076 female and male individuals (discovery: n = 649; replication: n = 427) comprising young, minimally medicated patients with clinical high-risk states for psychosis; patients with recent-onset depression or psychosis; and healthy volunteers. We employed multivariate sparse partial least squares analysis to detect parsimonious associations between combinations of items from the Childhood Trauma Questionnaire and gray matter volume and tested their generalizability via nested cross-validation as well as via external validation. We investigated the associations of these CT signatures with state (functioning, depressivity, quality of life), trait (personality), and sociodemographic levels. Results: We discovered signatures of age-dependent sexual abuse and sex-dependent physical and sexual abuse, as well as emotional trauma, which projected onto gray matter volume patterns in prefronto-cerebellar, limbic, and sensory networks. These signatures were associated with predominantly impaired clinical state- and trait-level phenotypes, while pointing toward an interaction between sexual abuse, age, urbanicity, and education. We validated the clinical profiles for all three CT signatures in the replication sample. Conclusions: Our results suggest distinct multilayered associations between partially age- and sex-dependent patterns of CT, distributed neuroanatomical networks, and clinical profiles. Hence, our study highlights how machine learning approaches can shape future, more fine-grained CT research

Defining High-risk Emergency Chief Complaints: Data-driven Triage for Low- and Middle-income Countries.

ObjectivesEmergency medicine in low- and middle-income countries (LMICs) is hindered by lack of research into patient outcomes. Chief complaints (CCs) are fundamental to emergency care but have only recently been uniquely codified for an LMIC setting in Uganda. It is not known whether CCs independently predict emergency unit patient outcomes.MethodsPatient data collected in a Ugandan emergency unit between 2009 and 2018 were randomized into validation and derivation data sets. A recursive partitioning algorithm stratified CCs by 3-day mortality risk in each group. The process was repeated in 10,000 bootstrap samples to create an averaged risk ranking. Based on this ranking, CCs were categorized as "high-risk" (>2× baseline mortality), "medium-risk" (between 2 and 0.5× baseline mortality), and "low-risk" (<0.5× baseline mortality). Risk categories were then included in a logistic regression model to determine if CCs independently predicted 3-day mortality.ResultsOverall, the derivation data set included 21,953 individuals with 7,313 in the validation data set. In total, 43 complaints were categorized, and 12 CCs were identified as high-risk. When controlled for triage data including age, sex, HIV status, vital signs, level of consciousness, and number of complaints, high-risk CCs significantly increased 3-day mortality odds ratio (OR = 2.39, 95% confidence interval [CI] = 1.95 to 2.93, p < 0.001) while low-risk CCs significantly decreased 3-day mortality odds (OR = 0.16, 95% CI = 0.09 to 0.29, p < 0.001).ConclusionsHigh-risk CCs were identified and found to predict increased 3-day mortality independent of vital signs and other data available at triage. This list can be used to expand local triage systems and inform emergency training programs. The methodology can be reproduced in other LMIC settings to reflect their local disease patterns