Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been ...reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein-protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10(-8) per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular biological pathways and functions.
Tourette syndrome (TS) is a severe neuropsychiatric disorder characterized by recurrent, involuntary physical and verbal tics. With a prevalence as high as 1% in children, a deeper understanding of ...the etiology of the disorder and contributions to risk is critical. Here, we cover the current body of knowledge in scientific literature regarding the genetics of TS. We first review the history and diagnostic criteria for TS cases. We then cover the prevalence, and begin to address the etiology of the disorder. We highlight long-standing evidence for a genetic contribution to TS risk from epidemiology studies focused on twins, families, and population-scale data. Finally, we summarize current large-scale genetic studies of TS along specific classes of genetic variation, including common variation, rare copy number variation, and de novo variation that impact protein-coding sequence. Although these variants do not account for the entirety of TS genetic risk, current evidence is clear that each class of variation is a factor in the overall risk architecture across TS cases.
The genetic risk factors of schizophrenia (SCZ), a severe psychiatric disorder, are not yet fully understood. Multiple lines of evidence suggest that mitochondrial dysfunction may play a role in SCZ, ...but comprehensive association studies are lacking. We hypothesized that variants in nuclear-encoded mitochondrial genes influence susceptibility to SCZ.
We conducted gene-based and gene-set analyses using summary association results from the Psychiatric Genomics Consortium Schizophrenia Phase 2 (PGC-SCZ2) genome-wide association study comprising 35,476 cases and 46,839 control subjects. We applied the MAGMA method to three sets of nuclear-encoded mitochondrial genes: oxidative phosphorylation genes, other nuclear-encoded mitochondrial genes, and genes involved in nucleus-mitochondria crosstalk. Furthermore, we conducted a replication study using the iPSYCH SCZ sample of 2290 cases and 21,621 control subjects.
In the PGC-SCZ2 sample, 1186 mitochondrial genes were analyzed, among which 159 had p values < .05 and 19 remained significant after multiple testing correction. A meta-analysis of 818 genes combining the PGC-SCZ2 and iPSYCH samples resulted in 104 nominally significant and nine significant genes, suggesting a polygenic model for the nuclear-encoded mitochondrial genes. Gene-set analysis, however, did not show significant results. In an in silico protein-protein interaction network analysis, 14 mitochondrial genes interacted directly with 158 SCZ risk genes identified in PGC-SCZ2 (permutation p = .02), and aldosterone signaling in epithelial cells and mitochondrial dysfunction pathways appeared to be overrepresented in this network of mitochondrial and SCZ risk genes.
This study provides evidence that specific aspects of mitochondrial function may play a role in SCZ, but we did not observe its broad involvement even using a large sample.
INTRODUCTION:
Subarachnoid hemorrhage (SAH) is a devastating neurological event affecting 1/10,000 adults globally with a mortality of more than 30%. SAH is financially straining for both the patient ...and caretaker due to its high morbidity, prolonged hospital stay, intensive treatments, and involved recovery. In this prospective study, we aim to quantify the total direct and indirect costs of SAH throughout the acute and subacute care periods.
METHODS:
Patients and their self-reported primary caregivers were prospectively followed for up to a year after the ictus hemorrhagic event, and queried monthly about expenses related to the recovery process. Additional clinical and cost information was obtained from the hospital finance department and directly from patient/caregiver follow-up interviews.
RESULTS:
Thirty-three patients were enrolled in this prospective study including 28 females (85%) and 5 males (15%) with a median (quartile range) age of 58 (47-66). Thirty-nine designated caregivers were also enrolled. The median ICU and hospital length of stay were 14 (11-19) and 19 (15-23) days, respectively. The median total cost for these patients was $135,568 ($38,082 - $644,688) and the median direct cost was $73,161 ($55,138 - $91,596) with a median expected patient payment of $114,453 ($70,772 -$204,855). The median percentage of direct costs attributed to the ICU was 40% (32-45). Patients with Medicare had smaller ranges of costs. Additionally indirect hospital costs reported were for travel related costs (hotels, ride shares, metro cards), toiletries, home modifications and medications ranging from $0 to $1000 a day.
CONCLUSION:
SAH is consistently a devastating neurological event affecting active members of society and their social networks. Its complicated course and recovery process can leave patients confined to a hospital for extended periods of time. As providers, we must investigate avenues to mitigate the costs and burdens patients and their support networks face.
In this paper, we address the problem of dataset quality in the context of Machine Learning (ML)-based critical systems. We briefly analyse the applicability of some existing standards dealing with ...data and show that the specificities of the ML context are neither properly captured nor taken into account. As a first answer to this concerning situation, we propose a dataset specification and verification process, and apply it on a signal recognition system from the railway domain. In addition, we also give a list of recommendations for the collection and management of datasets. This work is one step towards the dataset engineering process that will be required for ML to be used on safety critical systems.
There is an urgent need for expanding the number of brain banks serving psychiatric research. We describe here the Psychiatric Disorders arm of the Brain Bank of the Brazilian Aging Brain Study Group ...(Psy-BBBABSG), which is focused in bipolar disorder (BD) and obsessive compulsive disorder (OCD). Our protocol was designed to minimize limitations faced by previous initiatives, and to enable design-based neurostereological analyses. The Psy-BBBABSG first milestone is the collection of 10 brains each of BD and OCD patients, and matched controls. The brains are sourced from a population-based autopsy service. The clinical and psychiatric assessments were done by an expert team including psychiatrists, through an informant. One hemisphere was perfused-fixed to render an optimal fixation for conducting neurostereological studies. The other hemisphere was comprehensively dissected and frozen for molecular studies. In 20 months, we collected 36 brains. A final report was completed for 14 cases: 3 BDs, 4 major depressive disorders, 1 substance use disorder, 1 mood disorder NOS, 3 obsessive compulsive spectrum symptoms, 1 OCD and 1 schizophrenia. The majority were male (64%), and the average age at death was 67.2 ± 9.0 years. The average postmortem interval was 16 h. Three matched controls were collected. The pilot stage confirmed that the protocols are well fitted to reach our goals. Our unique autopsy source makes possible to collect a fairly number of high quality cases in a short time. Such a collection offers an additional to the international research community to advance the understanding on neuropsychiatric diseases.
Although quality of life (QoL) has become an important aspect of cancer rehabilitation, psychometric studies on thyroid cancer patients are rare. We performed a case-controlled study on QoL in ...patients with differentiated thyroid carcinoma (DTC). QoL was evaluated in 61 patients with a history of DTC diagnosed from < 1 to 23 yr earlier. An undetectable thyroglobulin (Tg) level after recombinant human TSH (rhTSH) testing was considered the best predictor of cure. QoL was evaluated by means of a general psychiatric interview, the self-rating Kellner Symptoms Questionnaire (KSQ) and the Hamilton Depression Scale (HDS). QoL was also evaluated in a control group of subjects on L-T4 therapy with a non-toxic multinodular goiter diagnosed from < 1 to 25 yr earlier. DTC and control subjects were similar in age, male-female distribution and concomitant psychiatric therapies. Per-week dosage of L-T4 was higher in DTC patients than in controls (p < 0.01). In neither group of subjects was there any correlation between current TSH levels or interval from diagnosis and KSQ or HDS scores. Only in DTC patients was there a positive correlation between age and KSQ (p < 0.05) or HDS (p < 0.01) scores. There was a significant difference in overall KSQ scores between DTC (33.4 +/- 2.1) and control (24.5 +/- 1.9; p < 0.01) subjects. The subscales of KSQ showed a significant inter-group difference. HDS scores were higher in DTC subjects (35.8 +/- 1.0) than in controls (30.0 +/- 1.1; p < 0.01). HDS score was significantly (p = 0.02) higher in female than in male DTC patients. In patients with papillary carcinoma there was a positive correlation between the MACIS (metastases, age, completeness, invasiveness, size) score and KSQ (p = 0.01) or HDS (p < 0.01) scores. After rhTSH testing, detectable Tg levels were found in 13% of DTC patients. In Tg-positive patients, KSQ and HDS scores were not different from those of Tg-negative patients. After an 8-14 month period, a significant decrease in the KSQ scale somatization (p = 0.02) was found in a sub-set of 31 DTC patients. In conclusion, even in the age of rhTSH testing, DTC patients suffer an impairment of their QoL, as noted when short-term L-T4 withdrawal was the gold standard. Longitudinal evaluation seems to indicate a slight improvement in QoL when safe rhTSH testing is extensively used in the management of the disease.
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