Leveraging wall-sized high-resolution displays for comparative genomics analyses of copy number variation

The scale of comparative genomics data frequently overwhelms current data visualization methods on conventional (desktop) displays. This paper describes two types of solution that take advantage of wall-sized high-resolution displays (WHirDs), which have orders of magnitude more display real estate (i.e., pixels) than desktop displays. The first allows users to view detailed graphics of copy number variation (CNV) that were output by existing software. A WHirD's resolution allowed a 10× increase in the granularity of bioinformatics output that was feasible for users to visually analyze, and this revealed a pattern that had previously been smoothed out from the underlying data. The second involved interactive visualization software that was innovative because it uses a music score metaphor to lay out CNV data, overcomes a perceptual distortion caused by amplification/deletion thresholds, uses filtering to reduce graphical data overload, and is the first comparative genomics visualization software that is designed to leverage a WHirD's real estate. In a field evaluation, a clinical user discovered a fundamental error in the way their data had been processed, and established confidence in the software by using it to 'find' known genetic patterns in hepatitis C-driven hepatocellular cancer

Porphyrins profile by high performance liquid chromatography/electrospray ionization tandem mass spectrometry for the diagnosis of porphyria

Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway. Most porphyria symptoms are nonspecific and occur intermittently; resulting frequently in missed diagnosis since the disease itself is a rare one. The aim of the study is toestablish a new reliable and accurate laboratory method for separation, identification and quantitation of urinary porphyrins by liquid chromatography tandem mass spectrometry (LC/MS/MS) and thereby the diagnosis of different porphyria types for the first time in Egypt. Screening by plasma fluorescence and quantitative determination of urinary porphyrins by high performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC/ESI/MS/MS) of 50 clinically suspected patients revealed one case of variegate porphyria and five cases of porphyria cutanea tarda. Plasma fluorescence scanning is a simple procedure that can be used as screening test to detect porphyria patients that require quantitation of urinary porphyrins as a second step. Quantitative determination of urinary porphyrins using HPLC/ESI/MS/MS and ion mapping techniques are applicable for the differential diagnosis of porphyria types, since each type has a characteristic porphyrins excretion profile. Quantitative determination of urinary porphyrins by HPLC/ESI/MS/MS used in this study is a modification for the method Stoev et al. while ion mapping technique is a new technique invented by the research team at the Biochemical Genetics Department

Validation of the AASLD recommendations for Classification of Oesophageal Varices in Clinical Practice

Background & Aims The American Association for the Study of Liver Diseases recommends the use of a 2‐grade classification system (small and large) to describe the size of oesophageal varices (OV). Data on observer agreement (OA) on this system are currently lacking. We aimed to evaluate this classification and compare it to the widely used 3‐grade classification (grade 1 ‘small’, grade 2 ‘medium’, grade 3 ‘large’) among operators of variable experience. Methods High‐definition video recordings of 100 patients with cirrhosis were prospectively collected using standardised criteria. Nine observers of variable experience performed independent evaluations of the videos in random order. OV were scored using both systems. All assessments were repeated a year later by the same observers to assess intra‐observer agreement. Results Interobserver agreement (all observers) using the 2‐grade and the 3‐grade system was k = 0.71 (95% CI: 0.64‐0.78) and k = 0.73 (95% CI: 0.66‐0.79) respectively. When using the 2‐grade system, intra‐observer agreement between hepatologists (n = 3), luminal gastroenterologists (n = 3) and trainee gastroenterologists (n = 3) was k = 0.89 (95% CI: 0.86‐0.91), k = 0.72 (95% CI: 0.67‐0.77), and k = 0.74 (95% CI: 0.67‐0.8) respectively. With the 3‐grade system; intra‐observer agreement between the same three subgroups were k = 0.9 (95% CI: 0.87‐0.92), k = 0.73 (95% CI: 0.68‐0.78), k = 0.77 (95% CI: 0.71‐0.82) respectively. Conclusions There was no difference in OA between the 2‐grade and 3‐grade classification systems. Hepatologists had significantly higher levels of consistency in grading OV. This may have implications to create alternative training models for residents and fellows in the recognition and grading of OV

Intraductal fully covered self-expanding metal stents in the management of post-liver transplant anastomotic strictures: a UK wide experience.

Background: Fully covered intraductal self-expanding metal stents (IDSEMS) have been well described in the management of post-liver transplant (LT) anastomotic strictures (ASs). Their antimigration waists and intraductal nature make them suited for deployment across the biliary anastomosis. Objectives: We conducted a multicentre study to analyse their use and efficacy in the management of AS. Design: This was a retrospective, multicentre observational study across nine tertiary centres in the United Kingdom. Methods: Consecutive patients who underwent endoscopic retrograde cholangiopancreatography with IDSEMS insertion were analysed retrospectively. Recorded variables included patient demographics, procedural characteristics, response to therapy and follow-up data. Results: In all, 162 patients (100 males, 62%) underwent 176 episodes of IDSEMS insertion for AS. Aetiology of liver disease in this cohort included hepatocellular carcinoma (n = 35, 22%), followed by alcohol-related liver disease (n = 29, 18%), non-alcoholic steatohepatitis (n = 20, 12%), primary biliary cholangitis (n = 15, 9%), acute liver failure (n = 13, 8%), viral hepatitis (n = 13, 8%) and autoimmune hepatitis (n = 12, 7%). Early AS occurred in 25 (15%) cases, delayed in 32 (20%) cases and late in 95 (59%) cases. Age at transplant was 54 years (range, 12-74), and stent duration was 15 weeks (range, 3 days-78 weeks). In total, 131 (81%) had complete resolution of stricture at endoscopic re-evaluation. Stricture recurrence was observed in 13 (10%) cases, with a median of 19 weeks (range, 4-88 weeks) after stent removal. At removal, there were 21 (12%) adverse events, 5 (3%) episodes of cholangitis and 2 (1%) of pancreatitis. In 11 (6%) cases, the removal wires unravelled, and 3 (2%) stents migrated. All were removed endoscopically. Conclusion: IDSEMS appears to be safe and highly efficacious in the management of post-LT AS, with low rates of AS recurrence

Validation of the aMAP score to predict hepatocellular carcinoma development in a cohort of alcohol‐related cirrhosis patients

Background and AimsThe aMAP score was recently devised to predict hepatocellular carcinoma (HCC) development. However, its performance was not tested in alcohol-related cirrhosis (ALC). We aimed to validate the aMAP score in a cohort of ALC patients.MethodStudy participants with ALC from a prior genome-wide association study were included. All participants had a history of high alcohol consumption. Cirrhosis was defined clinically, using fibroscan and/or histology. Patients were followed until the last liver imaging, HCC, liver transplantation (LT) or death with the latter two adjusted as competing risks.ResultsA total of 269 ALC patients were included: male (72.5%), Caucasian (98.9%), median age 56 years, and median Child-Pugh score 7. The median aMAP score was 60: 12.3% low-risk, 35.3% medium-risk and 52.4% high-risk. After a median follow-up of 41 months, 14 patients developed HCC, 27 received LT and 104 died. The aMAP score predicted HCC development (hazard ratio 1.12 per point increase, P < .001) with good separation of cumulative incidence function between risk groups. The area under the time-dependent receiver operating characteristics curve for predicting HCC development was 0.83 at 1 year and 0.82 at 5 years which was similar to ADRESS-HCC and Veterans Affairs Healthcare System scores respectively.ConclusionsWe validated the excellent performance of the aMAP score in ALC and affirm its applicability across wider aetiologies

Prediction of survival among patients receiving transarterial chemoembolization for hepatocellular carcinoma: A response-based approach

Background and aims: The heterogeneity of intermediate-stage hepatocellular carcinoma (HCC) and the widespread use of transarterial chemoembolization (TACE) outside recommended guidelines have encouraged the development of scoring systems that predict patient survival. The aim of this study was to build and validate statistical models that offer individualized patient survival prediction using response to TACE as a variable. Approach and results: Clinically relevant baseline parameters were collected for 4,621 patients with HCC treated with TACE at 19 centers in 11 countries. In some of the centers, radiological responses (as assessed by modified Response Evaluation Criteria in Solid Tumors [mRECIST]) were also accrued. The data set was divided into a training set, an internal validation set, and two external validation sets. A pre-TACE model ("Pre-TACE-Predict") and a post-TACE model ("Post-TACE-Predict") that included response were built. The performance of the models in predicting overall survival (OS) was compared with existing ones. The median OS was 19.9 months. The factors influencing survival were tumor number and size, alpha-fetoprotein, albumin, bilirubin, vascular invasion, cause, and response as assessed by mRECIST. The proposed models showed superior predictive accuracy compared with existing models (the hepatoma arterial embolization prognostic score and its various modifications) and allowed for patient stratification into four distinct risk categories whose median OS ranged from 7 months to more than 4 years. Conclusions: A TACE-specific and extensively validated model based on routinely available clinical features and response after first TACE permitted patient-level prognosticatio

Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers

BACKGROUND & AIMS: Carriage of rs738409:G in patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with PNPLA3 rs738409:G. This study explores the risk-associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. APPROACH AND RESULTS: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including: 1,031 with alcohol-related cirrhosis and HCC; 1,653 with alcohol-related cirrhosis without HCC; 2,588 alcohol misusers with no liver disease; and 899 healthy controls. Genetic associations with the risks for alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for both cirrhosis (OR 0.79 [95% CI 0.72-0.88], p=8.13×10-6) and HCC (OR 0.77 [95% CI 0.68-0.89], p=2.27×10-4), while carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR 1.70 [95% CI 1.54-1.88], p=1.52x10-26) and HCC (OR 1.77 [95% CI 1.58-1.98], p=2.31×10-23). These associations remained significant after adjusting for age, sex, body mass index, type II diabetes mellitus and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women but the protective effect against the subsequent development of HCC was only observed in men (p=1.72×10-4; ORallelic, 0.75; 95% CI, 0.64-0.87). CONCLUSIONS: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population

Healthcare costs of transarterial chemoembolization in the treatment of hepatocellular carcinoma

Waleed Fateen,1,2 Farooq Khan,1 Richard J O&rsquo;Neill,3 Martin W James,1 Stephen D Ryder,1 Guruprasad P Aithal1,2 1NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, 2Nottingham Digestive Diseases Centre, University of Nottingham, 3Department of Radiology, Nottingham University Hospitals, NHS Trust, Nottingham, UK Background: A meta-analysis comparing drug-eluting beads transarterial chemoembolization (DEB-TACE) with conventional transarterial chemoembolization (cTACE) has recently been published. On balance, no significant differences were found in terms of objective response and overall survival. The impact on healthcare costs had been studied in small series based on a hypothetical model and was in favor of DEB-TACE. We aimed to evaluate and compare healthcare costs and effectiveness of both modalities in a cohort of patients from Nottingham, UK.Methods: Using a dedicated radiology database, we identified all patients who had undergone cTACE or DEB-TACE between 2006 and 2012 at a single tertiary referral center based in Nottingham. We collected clinical data, including treatment response, postprocedure complications and 30-day mortality. Costing models were constructed to present both our local hospital perspective as well as the national health service position.Results: During our study period, 101 procedures were performed on 43 patients (76 cTACE procedures on 26 patients and 25 DEB-TACE procedures on 17 patients). Overall, 11/26 in cTACE and 5/17 in DEB-TACE group had progressive disease (p=0.52). Adverse events were seen in 6/76 cTACE compared with 7/25 DEB-TACE group (p=0.16). Based on the predetermined standard pathway there was an unadjusted average cost difference of &pound;3770.30 (TACE =&pound;9070.44, DEB-TACE =&pound;5300.14) in favor of the DEB-TACE. Results from our costing models indicated a &pound;2715.33 (95% CI &pound;580.88&ndash;4849.77) cost difference in favor of the same procedure.Conclusions: Even when the extra costs of DEB-TACE were considered, the overall treatment costs per patient were lower in relation to cTACE. Keywords: hepatocellular carcinoma, transarterial chemoembolization, healthcare costs, drug-eluting beads, objective respons

Characterisation of dysplastic liver nodules using low-pass DNA sequencing and detection of chromosome arm-level abnormalities in blood-derived cell-free DNA

High grade dysplasia carries significant risk of transformation to hepatocellular carcinoma (HCC). Despite this, at the current standard of care, all non-malignant hepatic nodules including high grade dysplastic nodules are managed similarly. This is partly related to difficulties in distinguishing high-risk pathology in the liver. We aimed to identify chromosome arm-level somatic copy number alterations (SCNAs) that characterise the transition of liver nodules along the cirrhosis-dysplasia-carcinoma axis. We validated our findings on an independent cohort using blood-derived cell-free DNA. A repository of non-cancer DNA sequences obtained from patients with HCC (n=389) was analysed to generate cut-off thresholds aiming to minimize false positive SCNAs. Tissue samples representing stages from the multistep process of hepatocarcinogenesis (n=184) were subjected to low-pass whole genome sequencing. Chromosome arm-level SCNAs were identified in liver cirrhosis, dysplastic nodules, and HCC to assess their discriminative capacity. Samples positive for 1q+ or 8q+ arm-level duplications were likely to be either HCC or high-grade dysplastic nodules as opposed to low grade dysplastic nodules or cirrhotic tissue with an Odds Ratio (OR) of 35.5 (95% CI 11.5–110) and 16 (95% CI 6.4–40.2) respectively (p<0.0001). In an independent cohort of patients recruited from Nottingham, UK, at least 2 out of 4 alterations (1q+, 4q-, 8p- and 8q+) were detectable in blood-derived cell-free DNA of patients with HCC (n=22) but none of the control patients with liver cirrhosis (n=9). Arm-level SCNAs on 1q+ or 8q+ are associated with high-risk liver pathology. These can be detected using low-pass sequencing of cell-free DNA isolated from blood which may be a future early cancer screening tool for patients with liver cirrhosis