Comparison of in silico strategies to prioritize rare genomic variants impacting RNA splicing for the diagnosis of genomic disorders

The development of computational methods to assess pathogenicity of pre-messenger RNA splicing variants is critical for diagnosis of human disease. We assessed the capability of eight algorithms, and a consensus approach, to prioritize 249 variants of uncertain significance (VUSs) that underwent splicing functional analyses. The capability of algorithms to differentiate VUSs away from the immediate splice site as being 'pathogenic' or 'benign' is likely to have substantial impact on diagnostic testing. We show that SpliceAI is the best single strategy in this regard, but that combined usage of tools using a weighted approach can increase accuracy further. We incorporated prioritization strategies alongside diagnostic testing for rare disorders. We show that 15% of 2783 referred individuals carry rare variants expected to impact splicing that were not initially identified as 'pathogenic' or 'likely pathogenic'; one in five of these cases could lead to new or refined diagnoses

Gender differences and determinants of health related quality of life in coronary patients: a follow-up study

<p>Abstract</p> <p>Background</p> <p>The role of gender differences in Health Related Quality Life (HRQL) in coronary patients is controversial, so understanding the specific determinants of HRQL in men and women might be of clinical importance. The aim of this study was to know the gender differences in the evolution of HRQL at 3 and 6 months after a coronary event, and to identify the key clinical, demographic and psychological characteristics of each gender associated with these changes.</p> <p>Methods</p> <p>A follow-up study was carried out, and 175 patients (112 men and 63 women) with acute myocardial infarction (AMI) or unstable angina were studied. The SF-36v1 health questionnaire was used to assess HRQL, and the GHQ-28 (General Health Questionnaire) to measure mental health during follow-up. To study the variables related to changes in HRQL, generalized estimating equation (GEE) models were performed.</p> <p>Results</p> <p>Follow-up data were available for 55 men and 25 women at 3 months, and for 35 men and 12 women at 6 months. Observations included: a) Revascularization was performed later in women. b) The frequency of rehospitalization between months 3 and 6 of follow-up was higher in women c) Women had lower baseline scores in the SF-36. d) Men had progressed favourably in most of the physical dimensions of the SF-36 at 6 months, while at the same time women's scores had only improved for Physical Component Summary, Role Physical and Social Functioning; e) the variables determining the decrease in HRQL in men were: worse mental health and angina frequency; and in women: worse mental health, history of the disease, revascularization, and angina frequency.</p> <p>Conclusions</p> <p>There are differences in the evolution of HRQL, between men and women after a coronary attack. Mental health is the determinant most frequently associated with HRQL in both genders. However, other clinical determinants of HRQL differed with gender, emphasizing the importance of individualizing the intervention and the content of rehabilitation programs. Likewise, the recognition and treatment of mental disorders in these patients could be crucial.</p

Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial

BACKGROUND: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. METHODS: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. RESULTS: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. CONCLUSIONS: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin

Genomic Analysis of Individual Differences in Ethanol Drinking: Evidence for Non-Genetic Factors in C57BL/6 Mice

Genetic analysis of factors affecting risk to develop excessive ethanol drinking has been extensively studied in humans and animal models for over 20 years. However, little progress has been made in determining molecular mechanisms underlying environmental or non-genetic events contributing to variation in ethanol drinking. Here, we identify persistent and substantial variation in ethanol drinking behavior within an inbred mouse strain and utilize this model to identify gene networks influencing such “non-genetic” variation in ethanol intake. C57BL/6NCrl mice showed persistent inter-individual variation of ethanol intake in a two-bottle choice paradigm over a three-week period, ranging from less than 1 g/kg to over 14 g/kg ethanol in an 18 h interval. Differences in sweet or bitter taste susceptibility or litter effects did not appreciably correlate with ethanol intake variation. Whole genome microarray expression analysis in nucleus accumbens, prefrontal cortex and ventral midbrain region of individual animals identified gene expression patterns correlated with ethanol intake. Results included several gene networks previously implicated in ethanol behaviors, such as glutamate signaling, BDNF and genes involved in synaptic vesicle function. Additionally, genes functioning in epigenetic chromatin or DNA modifications such as acetylation and/or methylation also had expression patterns correlated with ethanol intake. In verification for the significance of the expression findings, we found that a histone deacetylase inhibitor, trichostatin A, caused an increase in 2-bottle ethanol intake. Our results thus implicate specific brain regional gene networks, including chromatin modification factors, as potentially important mechanisms underlying individual variation in ethanol intake

A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology

BACKGROUND: Understanding variations in the incidence of schizophrenia is a crucial step in unravelling the aetiology of this group of disorders. The aims of this review are to systematically identify studies related to the incidence of schizophrenia, to describe the key features of these studies, and to explore the distribution of rates derived from these studies. METHODS: Studies with original data related to the incidence of schizophrenia (published 1965–2001) were identified via searching electronic databases, reviewing citations and writing to authors. These studies were divided into core studies, migrant studies, cohort studies and studies based on Other Special Groups. Between- and within-study filters were applied in order to identify discrete rates. Cumulative plots of these rates were made and these distributions were compared when the underlying rates were sorted according to sex, urbanicity, migrant status and various methodological features. RESULTS: We identified 100 core studies, 24 migrant studies, 23 cohort studies and 14 studies based on Other Special Groups. These studies, which were drawn from 33 countries, generated a total of 1,458 rates. Based on discrete core data for persons (55 studies and 170 rates), the distribution of rates was asymmetric and had a median value (10%–90% quantile) of 15.2 (7.7–43.0) per 100,000. The distribution of rates was significantly higher in males compared to females; the male/female rate ratio median (10%–90% quantile) was 1.40 (0.9–2.4). Those studies conducted in urban versus mixed urban-rural catchment areas generated significantly higher rate distributions. The distribution of rates in migrants was significantly higher compared to native-born; the migrant/native-born rate ratio median (10%–90% quantile) was 4.6 (1.0–12.8). Apart from the finding that older studies reported higher rates, other study features were not associated with significantly different rate distributions (e.g. overall quality, methods related to case finding, diagnostic confirmation and criteria, the use of age-standardization and age range). CONCLUSIONS: There is a wealth of data available on the incidence of schizophrenia. The width and skew of the rate distribution, and the significant impact of sex, urbanicity and migrant status on these distributions, indicate substantial variations in the incidence of schizophrenia

Divergent representations of manipulable and non-manipulable objects revealed with repetition blindness

Neuroimaging and neuropsychological studies suggest that manipulable objects (i.e., objects associated with particular actions) have distributed representations that reflect not only their visual features but also the actions they afford. This study used rapid serial visual presentation (RSVP) to investigate the nature of the representations underlying identification of manipulable objects. When stimuli are presented at RSVP rates, items repeated within 500 msec of each other are frequently missed, a phenomenon known as repetition blindness (RB). RB is thought to occur because repeated stimuli activate the same abstract memory representation (type) but are not individuated into distinct visual episodes (tokens) due to the spatio-temporal constraints of RSVP. In two experiments that employed different stimulus sets (photographs vs line drawings), observers viewed RSVP streams containing three objects and six masks and attempted to identify the objects. The first and third objects in the stream were either the same object repeated, or distinct objects, and were either Action (i.e., manipulable) or Non-Action (non-manipulable) objects. There were two main findings. First, joint accuracy for reporting two distinct Action objects was considerably lower than for Non-Action objects, even when the two object classes were equated in terms of ease of identification. Second, whereas Non-Action objects induced RB independent of the objects' orientation, in keeping with previous findings (Harris & Dux, 2005; Hayward et al., in press), there was no RB at all for Action objects. Instead, significant priming was obtained when an Action object was repeated in the same orientation. Taken together, these findings implicate independent sources of visual and motor information, which require integration for successful identification. Under RSVP conditions, this renders Action objects vulnerable to interference from other objects associated with conflicting motor programs, but facilitates individuation of repeated objects associated with the same action