Systematic Overestimation of Machine Learning Performance in Neuroimaging Studies of Depression

We currently observe a disconcerting phenomenon in machine learning studies in psychiatry: While we would expect larger samples to yield better results due to the availability of more data, larger machine learning studies consistently show much weaker performance than the numerous small-scale studies. Here, we systematically investigated this effect focusing on one of the most heavily studied questions in the field, namely the classification of patients suffering from Major Depressive Disorder (MDD) and healthy controls. Drawing upon a balanced sample of $N = 1,868$ MDD patients and healthy controls from our recent international Predictive Analytics Competition (PAC), we first trained and tested a classification model on the full dataset which yielded an accuracy of 61%. Next, we mimicked the process by which researchers would draw samples of various sizes ($N=4$ to $N=150$) from the population and showed a strong risk of overestimation. Specifically, for small sample sizes ($N=20$), we observe accuracies of up to 95%. For medium sample sizes ($N=100$) accuracies up to 75% were found. Importantly, further investigation showed that sufficiently large test sets effectively protect against performance overestimation whereas larger datasets per se do not. While these results question the validity of a substantial part of the current literature, we outline the relatively low-cost remedy of larger test sets

Targeting a Versatile Actuator for EU-DEMO: Real Time Monitoring of Pellet Delivery to Facilitate Burn Control

Core particle fueling, an essential task in the European demonstration fusion power plant EU-DEMO, relies on adequate pellet injection. However, pellets are fragile objects, and their delivery efficiency can hardly be assumed to be unity. Exploring kinetic control of the EU-DEMO1 scenario indicates that such missed-out pellets do cause a considerable problem for keeping a burning plasma. Missed-out pellets can cause a severe drop of plasma density that in turn results in a potential drastic loss of burn power. Efforts are under way at the ASDEX Upgrade (AUG) tokamak aiming to provide real-time monitoring of pellet arrival and announcement of missed-out cases to the control systems. To further optimize the controllers, system identification experiments have been performed to identify the dynamic response of the system to the actuator

Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

Background Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes. Methods We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants. Results Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects. Conclusions Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application

Massive migration from the steppe is a source for Indo-European languages in Europe

We generated genome-wide data from 69 Europeans who lived between 8,000-3,000 years ago by enriching ancient DNA libraries for a target set of almost four hundred thousand polymorphisms. Enrichment of these positions decreases the sequencing required for genome-wide ancient DNA analysis by a median of around 250-fold, allowing us to study an order of magnitude more individuals than previous studies and to obtain new insights about the past. We show that the populations of western and far eastern Europe followed opposite trajectories between 8,000-5,000 years ago. At the beginning of the Neolithic period in Europe, ~8,000-7,000 years ago, closely related groups of early farmers appeared in Germany, Hungary, and Spain, different from indigenous hunter-gatherers, whereas Russia was inhabited by a distinctive population of hunter-gatherers with high affinity to a ~24,000 year old Siberian6 . By ~6,000-5,000 years ago, a resurgence of hunter-gatherer ancestry had occurred throughout much of Europe, but in Russia, the Yamnaya steppe herders of this time were descended not only from the preceding eastern European hunter-gatherers, but from a population of Near Eastern ancestry. Western and Eastern Europe came into contact ~4,500 years ago, as the Late Neolithic Corded Ware people from Germany traced ~3/4 of their ancestry to the Yamnaya, documenting a massive migration into the heartland of Europe from its eastern periphery. This steppe ancestry persisted in all sampled central Europeans until at least ~3,000 years ago, and is ubiquitous in present-day Europeans. These results provide support for the theory of a steppe origin of at least some of the Indo-European languages of Europe

Involvement of the Intrinsic/Default System in Movement-Related Self Recognition

The question of how people recognize themselves and separate themselves from the environment and others has long intrigued philosophers and scientists. Recent findings have linked regions of the ‘default brain’ or ‘intrinsic system’ to self-related processing. We used a paradigm in which subjects had to rely on subtle sensory-motor synchronization differences to determine whether a viewed movement belonged to them or to another person, while stimuli and task demands associated with the “responded self” and “responded other” conditions were precisely matched. Self recognition was associated with enhanced brain activity in several ROIs of the intrinsic system, whereas no differences emerged within the extrinsic system. This self-related effect was found even in cases where the sensory-motor aspects were precisely matched. Control conditions ruled out task difficulty as the source of the differential self-related effects. The findings shed light on the neural systems underlying bodily self recognition

Patients with schizophrenia show deficits of working memory maintenance components in circuit-specific tasks

Working memory (WM) deficits are a neuropsychological core finding in patients with schizophrenia and also supposed to be a potential endophenotype of schizophrenia. Yet, there is a large heterogeneity between different WM tasks which is partly due to the lack of process specificity of the tasks applied. Therefore, we investigated WM functioning in patients with schizophrenia using process- and circuit-specific tasks. Thirty-one patients with schizophrenia and 47 controls were tested with respect to different aspects of verbal and visuospatial working memory using modified Sternberg paradigms in a computer-based behavioural experiment. Total group analysis revealed significant impairment of patients with schizophrenia in each of the tested WM components. Furthermore, we were able to identify subgroups of patients showing different patterns of selective deficits. Patients with schizophrenia exhibit specific and, in part, selective WM deficits with indirect but conclusive evidence of dysfunctions of the underlying neural networks. These deficits are present in tasks requiring only maintenance of verbal or visuospatial information. In contrast to a seemingly global working memory deficit, individual analysis revealed differential patterns of working memory impairments in patients with schizophrenia

Revising mtDNA haplotypes of the ancient Hungarian conquerors with next generation sequencing

As part of the effort to create a high resolution representative sequence database of the medieval Hungarian conquerors we have resequenced the entire mtDNA genome of 24 published ancient samples with Next Generation Sequencing, whose haplotypes had been previously determined with traditional PCR based methods. We show that PCR based methods are prone to erroneous haplotype or haplogroup determination due to ambiguous sequence reads, and many of the resequenced samples had been classified inaccurately. The SNaPshot method applied with published ancient DNA authenticity criteria is the most straightforward and cheapest PCR based approach for testing a large number of coding region SNP-s, which greatly facilitates correct haplogroup determination

PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features.

PUF60 encodes a nucleic acid-binding protein, a component of multimeric complexes regulating RNA splicing and transcription. In 2013, patients with microdeletions of chromosome 8q24.3 including PUF60 were found to have developmental delay, microcephaly, craniofacial, renal and cardiac defects. Very similar phenotypes have been described in six patients with variants in PUF60, suggesting that it underlies the syndrome. We report 12 additional patients with PUF60 variants who were ascertained using exome sequencing: six through the Deciphering Developmental Disorders Study and six through similar projects. Detailed phenotypic analysis of all patients was undertaken. All 12 patients had de novo heterozygous PUF60 variants on exome analysis, each confirmed by Sanger sequencing: four frameshift variants resulting in premature stop codons, three missense variants that clustered within the RNA recognition motif of PUF60 and five essential splice-site (ESS) variant. Analysis of cDNA from a fibroblast cell line derived from one of the patients with an ESS variants revealed aberrant splicing. The consistent feature was developmental delay and most patients had short stature. The phenotypic variability was striking; however, we observed similarities including spinal segmentation anomalies, congenital heart disease, ocular colobomata, hand anomalies and (in two patients) unilateral renal agenesis/horseshoe kidney. Characteristic facial features included micrognathia, a thin upper lip and long philtrum, narrow almond-shaped palpebral fissures, synophrys, flared eyebrows and facial hypertrichosis. Heterozygote loss-of-function variants in PUF60 cause a phenotype comprising growth/developmental delay and craniofacial, cardiac, renal, ocular and spinal anomalies, adding to disorders of human development resulting from aberrant RNA processing/spliceosomal function

Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta

PURPOSE: Thoracic aortic aneurysm/aortic dissection (TAAD) is a disorder with highly variable age of onset and phenotype. We sought to determine the prevalence of pathogenic variants in TAAD-associated genes in a mixed cohort of sporadic and familial TAAD patients and identify relevant genotype–phenotype relationships. METHODS: We used a targeted polymerase chain reaction and next-generation sequencing–based panel for genetic analysis of 15 TAAD-associated genes in 1,025 unrelated TAAD cases. RESULTS: We identified 49 pathogenic or likely pathogenic (P/LP) variants in 47 cases (4.9% of those successfully sequenced). Almost half of the variants were in nonsyndromic cases with no known family history of aortic disease. Twenty-five variants were within FBN1 and two patients were found to harbor two P/LP variants. Presence of a related syndrome, younger age at presentation, family history of aortic disease, and involvement of the ascending aorta increased the risk of carrying a P/LP variant. CONCLUSION: Given the poor prognosis of TAAD that is undiagnosed prior to acute rupture or dissection, genetic analysis of both familial and sporadic cases of TAAD will lead to new diagnoses, more informed management, and possibly reduced mortality through earlier, preclinical diagnosis in genetically determined cases and their family members