GeneTIER: prioritization of candidate disease genes using tissue-specific gene expression profiles.

Motivation In attempts to determine the genetic causes of human disease, researchers are often faced with a large number of candidate genes. Linkage studies can point to a genomic region containing hundreds of genes, while the high-throughput sequencing approach will often identify a great number of non-synonymous genetic variants. Since systematic experimental verification of each such candidate gene is not feasible, a method is needed to decide which genes are worth investigating further. Computational gene prioritization presents itself as a solution to this problem, systematically analyzing and sorting each gene from the most to least likely to be the disease-causing gene, in a fraction of the time it would take a researcher to perform such queries manually. Results Here we present GeneTIER (Gene TIssue Expression Ranker), a new web-based application for candidate gene prioritization. GeneTIER replaces knowledge-based inference traditionally used in candidate disease gene prioritization applications with experimental data from tissue-specific gene expression datasets and thus largely overcomes the bias towards the better characterized genes/diseases that commonly afflict other methods. We show that our approach is capable of accurate candidate gene prioritization and illustrate its strengths and weaknesses using case study examples. Availability and Implementation Freely available on the web at http://dna.leeds.ac.uk/GeneTIER/ Contact: [email protected]

Economic burden of disease of uncontrolled acromegalic patients : the acromegaly Italian collaborative study group

Background: Acromegaly is a rare, serious and disabling disease associated with increased mortality if not properly treated. The objective of this study was to estimate indirect and direct costs associated to uncontrolled acromegalic patients in Italy. Methods: a specific questionnaire was developed in order to obtain specific information from the patient perspective and administrated to subsequent patients treated in 17 Italian endocrinology centres. Indirect cost from patients and caregivers perspective were estimated considering the Human Capital Approach while direct cost were evaluated considering the patients perspective. assuming that our sample were representative of the general uncontrolled acromegalic patients. Results: 86 patients were enrolled in the study and complete the questionnaire. Of these 51.16% were employed, 23.26% were unemployed for reasons unrelated to the illness, 8,14% were unemployed due to the illness and 17.44% were inactive. The total costs per patient amounted to about € 3,832 per year, of which 5.1% are mobility costs, while the indirect costs come to € 7.7 million, of which 45.7% is due to illness-related to unemployment. Conclusions: To our knowledge, this study represents the first attempt to quantify the costs of uncontrolled acromegalic patients in Italy

Structure of the TPR Domain of AIP: Lack of Client Protein Interaction with the C-Terminal alpha-7 Helix of the TPR Domain of AIP Is Sufficient for Pituitary Adenoma Predisposition

PMCID: PMC3534021This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Evidence based medicine as science

Evidence based medicine has claimed to be science on a number of occasions but it is not clear that this status is deserved. Within philosophy of science four main theories about the nature of science are historically recognised: inductivism, falsificationism, Kuhnian paradigms and research programmes. If evidence based medicine is science knowledge claims should be derived using a process that corresponds to one of these theories. This paper analyses whether this is the case. In the first section, different theories about the nature of science are introduced. In the second section, the claim that evidence based medicine is science is reinterpreted as the claim that knowledge claims derived from randomised controlled trails and meta-analyses are science. In the third section the knowledge claims valued within evidence based medicine are considered from the perspective of inductivism, falsificationism, Kuhnian paradigms and research programmes. In the final section possible counter arguments are considered. It is argued that the knowledge claims valued by evidence based medicine are not justified using inductivism, falsificationism, Kuhnian paradigms or research programmes. If these are the main criteria for evaluating if something is science or not, evidence based medicine does not meet these criteria

Studying Cat (Felis catus) Diabetes: Beware of the Acromegalic Imposter

Naturally occurring diabetes mellitus (DM) is common in domestic cats (Felis catus). It has been proposed as a model for human Type 2 DM given many shared features. Small case studies demonstrate feline DM also occurs as a result of insulin resistance due to a somatotrophinoma. The current study estimates the prevalence of hypersomatotropism or acromegaly in the largest cohort of diabetic cats to date, evaluates clinical presentation and ease of recognition. Diabetic cats were screened for hypersomatotropism using serum total insulin-like growth factor-1 (IGF-1; radioimmunoassay), followed by further evaluation of a subset of cases with suggestive IGF-1 (>1000 ng/ml) through pituitary imaging and/ or histopathology. Clinicians indicated pre-test suspicion for hypersomatotropism. In total 1221 diabetic cats were screened; 319 (26.1%) demonstrated a serum IGF-1>1000 ng/ml (95% confidence interval: 23.6-28.6%). Of these cats a subset of 63 (20%) underwent pituitary imaging and 56/63 (89%) had a pituitary tumour on computed tomography; an additional three on magnetic resonance imaging and one on necropsy. These data suggest a positive predictive value of serum IGF-1 for hypersomatotropism of 95% (95% confidence interval: 90-100%), thus suggesting the overall hypersomatotropism prevalence among UK diabetic cats to be 24.8% (95% confidence interval: 21.2-28.6%). Only 24% of clinicians indicated a strong pre-test suspicion; most hypersomatotropism cats did not display typical phenotypical acromegaly signs. The current data suggest hypersomatotropism screening should be considered when studying diabetic cats and opportunities exist for comparative acromegaly research, especially in light of the many detected communalities with the human disease

Mitochondrial and nuclear genes suggest that stony corals are monophyletic but most families of stony corals are not (Order Scleractinia, Class Anthozoa, Phylum Cnidaria)

Modern hard corals (Class Hexacorallia; Order Scleractinia) are widely studied because of their fundamental role in reef building and their superb fossil record extending back to the Triassic. Nevertheless, interpretations of their evolutionary relationships have been in flux for over a decade. Recent analyses undermine the legitimacy of traditional suborders, families and genera, and suggest that a non-skeletal sister clade (Order Corallimorpharia) might be imbedded within the stony corals. However, these studies either sampled a relatively limited array of taxa or assembled trees from heterogeneous data sets. Here we provide a more comprehensive analysis of Scleractinia (127 species, 75 genera, 17 families) and various outgroups, based on two mitochondrial genes (cytochrome oxidase I, cytochrome b), with analyses of nuclear genes (ßtubulin, ribosomal DNA) of a subset of taxa to test unexpected relationships. Eleven of 16 families were found to be polyphyletic. Strikingly, over one third of all families as conventionally defined contain representatives from the highly divergent "robust" and "complex" clades. However, the recent suggestion that corallimorpharians are true corals that have lost their skeletons was not upheld. Relationships were supported not only by mitochondrial and nuclear genes, but also often by morphological characters which had been ignored or never noted previously. The concordance of molecular characters and more carefully examined morphological characters suggests a future of greater taxonomic stability, as well as the potential to trace the evolutionary history of this ecologically important group using fossils

A Pilot study of the Sharing Risk Information Tool (ShaRIT) for Families with Hereditary Breast and Ovarian Cancer Syndrome

<p>Abstract</p> <p>Background</p> <p>Individuals who carry deleterious BRCA mutations face significantly elevated risks of breast, ovarian, and other cancers. These individuals are also responsible for informing relatives of their increased risk for carrying the family BRCA mutation. Few interventions have been developed to facilitate this family communication process.</p> <p>Methods</p> <p>We developed the Sharing Risk Information Tool (ShaRIT), a personalized educational intervention, to support BRCA carriers as they discuss BRCA positive results and their implications with relatives. We conducted a pilot study of 19 BRCA carriers identified through the University of California San Francisco Cancer Risk Program. Our study had two aims: 1) to assess the feasibility and acceptability of ShaRIT, and 2) describe characteristics associated with increased family communication and BRCA testing. Participants in our study were divided into two groups: those who had not received ShaRIT as part of their genetic counseling protocol (control group, n = 10) and those who received ShaRIT (n = 9).</p> <p>Results</p> <p>All 9 women who received ShaRIT reported that it was a useful resource. Characteristics associated with increased sharing and testing included: female gender, degree of relationship, and frequency of communication. Increased pedigree knowledge showed a trend toward higher rates of sharing.</p> <p>Conclusions</p> <p>Both participants and genetic counselors considered ShaRIT a well-received, comprehensive tool for disseminating individual risk information and clinical care guidelines to Hereditary Breast and Ovarian Cancer Syndrome families. Because of this, ShaRIT has been incorporated as standard of care at our institution. In the future we hope to evaluate the effects of ShaRIT on family communication and family testing in larger populations of BRCA positive families.</p

Adverse anthropometric risk profile in biochemically controlled acromegalic patients: comparison with an age- and gender-matched primary care population

GH and IGF-1 play an important role in the regulation of metabolism and body composition. In patients with uncontrolled acromegaly, cardiovascular morbidity and mortality are increased but are supposed to be normalised after biochemical control is achieved. We aimed at comparing body composition and the cardiovascular risk profile in patients with controlled acromegaly and controls. A cross-sectional study. We evaluated anthropometric parameters (height, weight, body mass index (BMI), waist and hip circumference, waist to height ratio) and, additionally, cardiovascular risk biomarkers (fasting plasma glucose, HbA1c, triglycerides, total cholesterol, HDL, LDL, and lipoprotein (a), in 81 acromegalic patients (58% cured) compared to 320 age- and gender-matched controls (ratio 1:4), sampled from the primary care patient cohort DETECT. The whole group of 81 acromegalic patients presented with significantly higher anthropometric parameters, such as weight, BMI, waist and hip circumference, but with more favourable cardiovascular risk biomarkers, such as fasting plasma glucose, total cholesterol, triglycerides and HDL levels, in comparison to their respective controls. Biochemically controlled acromegalic patients again showed significantly higher measurements of obesity, mainly visceral adiposity, than age- and gender-matched control patients (BMI 29.5 ± 5.9 vs. 27.3 ± 5.8 kg/m2; P = 0.020; waist circumference 100.9 ± 16.8 vs. 94.8 ± 15.5 cm; P = 0.031; hip circumference 110.7 ± 9.9 vs. 105.0 ± 11.7 cm; P = 0.001). No differences in the classical cardiovascular biomarkers were detected except for fasting plasma glucose and triglycerides. This effect could not be attributed to a higher prevalence of type 2 diabetes mellitus in the acromegalic patient group, since stratified analyses between the subgroup of patients with acromegaly and controls, both with type 2 diabetes mellitus, revealed that there were no significant differences in the anthropometric measurements. Biochemically cured acromegalic patients pertain an adverse anthropometric risk profile, mainly because of elevated adiposity measurements, such as BMI, waist and hip circumference, compared to an age- and gender-matched primary care population