Although nonalcoholic fatty liver disease (NAFLD) is closely linked to obesity, around 10%‐20% of nonobese Americans and Asians still develop NAFLD. Data on this special group are limited. We ...therefore studied the severity and clinical outcomes of nonobese NAFLD patients. Consecutive NAFLD patients who underwent liver biopsy were prospectively recruited. We used the NASH Clinical Research Network system to score the histology. The Asian body mass index cutoff of 25 kg/m2 was used to define nonobese NAFLD. Among 307 recruited NAFLD patients, 72 (23.5%) were nonobese. Compared to obese patients, nonobese patients had lower NAFLD activity score (3.3 ± 1.3 vs. 3.8 ± 1.2; P = 0.019), mainly contributed by steatosis (1.7 ± 0.8 vs. 2.0 ± 0.8; P = 0.014) and presence of hepatocyte ballooning (60.9% vs. 73.4%; P = 0.045). Similarly, nonobese patients had lower fibrosis stage (1.3 ± 1.5 vs. 1.7 ± 1.4; P = 0.004), serum cytokeratin‐18 fragments (283 vs. 404 U/L; P < 0.001) and liver stiffness measurement by transient elastography (6.3 vs. 8.6 kilopascals; P < 0.001). By multivariate analysis in nonobese patients, only elevated serum triglyceride level was independently associated with higher NAFLD activity score (adjusted odds ratio OR, 1.644; P = 0.021), whereas elevated creatinine level was the only factor associated with advanced fibrosis (adjusted OR, 1.044; P = 0.025). After a median follow‐up of 49 months, 6 patients died, 2 developed hepatocellular carcinoma, and 1 had liver failure, all of whom were in the obese group. Conclusion: Nonobese NAFLD patients tend to have less‐severe disease and may have a better prognosis than obese patients. Hypertriglyceridemia and higher creatinine are the key factors associated with advanced liver disease in nonobese patients. (Hepatology 2017;65:54‐64)
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in affluent countries. Accurate noninvasive tests for liver injury are urgently needed. The aim of this study was to ...evaluate the accuracy of transient elastography for the diagnosis of fibrosis and cirrhosis in patients with NAFLD and to study factors associated with discordance between transient elastography and histology. Two hundred forty‐six consecutive patients from two ethnic groups had successful liver stiffness measurement and satisfactory liver biopsy specimens. The area under the receiver‐operating characteristics curve (AUROC) of transient elastography for F3 or higher and F4 disease was 0.93 and 0.95, respectively, and was significantly higher than that of the aspartate aminotransferase–to–alanine aminotransferase ratio, aspartate aminotransferase–to–platelet ratio index, FIB‐4, BARD, and NAFLD fibrosis scores (AUROC ranged from 0.62 to 0.81, P < 0.05 for all comparisons). At a cutoff value of 7.9 kPa, the sensitivity, specificity, and positive and negative predictive values for F3 or greater disease were 91%, 75%, 52%, and 97%, respectively. Liver stiffness was not affected by hepatic steatosis, necroinflammation, or body mass index. Discordance of at least two stages between transient elastography and histology was observed in 33 (13.4%) patients. By multivariate analysis, liver biopsy length less than 20 mm and F0‐2 disease were associated with discordance. Conclusion: Transient elastography is accurate in most NAFLD patients. Unsatisfactory liver biopsy specimens rather than transient elastography technique account for most cases of discordance. With high negative predictive value and modest positive predictive value, transient elastography is useful as a screening test to exclude advanced fibrosis. Liver biopsy may be considered in NAFLD patients with liver stiffness of at least 7.9 kPa. (HEPATOLOGY 2010;51:454–462.)
Controlled attenuation parameter (CAP) evaluated with transient elastography (FibroScan) is a recent method for non-invasive assessment of steatosis. Its usefulness in non-alcoholic fatty liver ...disease (NAFLD) is unknown. We prospectively investigated the performance of CAP for the diagnosis of steatosis in NAFLD, factors associated with discordances between CAP and steatosis grades, and relationships between CAP and clinical or biological parameters.
All CAP examinations performed in NAFLD patients with a liver biopsy performed within 1 week of CAP measurement were included. Liver biopsies were assessed for activity and fibrosis stage, NAFLD activity score, and steatosis graded as follows: S0, steatosis < 5%; S1, 5-33%; S2, 34-66%; S3, >66%.
Two hundred sixty-one patients (59% male, age 56 years) from two ethnic groups were included. No patient had steatosis < 5%. The area under the receiver-operating characteristics curve of CAP for steatosis ≥S2 and S3 was 0.80 and 0.66, respectively. At a cut-off value of 310 dB/m, the sensitivity, specificity, and positive and negative predictive values for ≥S2 steatosis were 79%, 71%, 86%, and 71%, respectively. Discordance of at least one grade between CAP and steatosis was observed in 81 patients. By multivariate analysis, only steatosis S2S3 was associated with no discordance. By multivariate analysis, only BMI ≥ 30 kg/m(2) was significantly associated with CAP > 310 dB/m.
The association of CAP with steatosis, especially in patients with non-alcoholic steatohepatitis, and with elevated BMI could be useful for the diagnosis and follow-up of NAFLD patients.
ObjectiveThe latest model of vibration-controlled transient elastography (VCTE) automatically selects M or XL probe according to patients’ body built. We aim to test the application of a unified ...interpretation of VCTE results with probes appropriate for the body mass index (BMI) and hypothesise that this approach is not affected by hepatic steatosis.DesignWe prospectively recruited 496 patients with non-alcoholic fatty liver disease who underwent VCTE by both M and XL probes within 1 week before liver biopsy.Results391 (78.8%) and 433 (87.3%) patients had reliable liver stiffness measurement (LSM) (10 successful acquisitions and IQR:median ratio ≤0.30) by M and XL probes, respectively (p<0.001). The area under the receiver operating characteristic curves was similar between the two probes (0.75–0.88 for F2–4, 0.83–0.91 for F4). When used in the same patient, LSM by XL probe was lower than that by M probe (mean difference 2.3 kPa). In contrast, patients with BMI ≥30 kg/m2 had higher LSM regardless of the probe used. When M and XL probes were used in patients with BMI <30 and ≥30 kg/m2, respectively, they yielded nearly identical median LSM at each fibrosis stage and similar diagnostic performance. Severe steatosis did not increase LSM or the rate of false-positive diagnosis by XL probe.ConclusionHigh BMI but not severe steatosis increases LSM. The same LSM cut-offs can be used without further adjustment for steatosis when M and XL probes are used according to the appropriate BMI.
Artificial intelligence (AI) has become increasingly widespread in our daily lives, including healthcare applications. AI has brought many new insights into better ways we care for our patients with ...chronic liver disease, including non‐alcoholic fatty liver disease and liver fibrosis. There are multiple ways to apply the AI technology on top of the conventional invasive (liver biopsy) and noninvasive (transient elastography, serum biomarkers, or clinical prediction models) approaches. In this review article, we discuss the principles of applying AI on electronic health records, liver biopsy, and liver images. A few common AI approaches include logistic regression, decision tree, random forest, and XGBoost for data at a single time stamp, recurrent neural networks for sequential data, and deep neural networks for histology and images.
Liver stiffness measurement (LSM) frequently overestimates the severity of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). Controlled attenuation parameter (CAP) is a new parameter ...provided by the same machine used for LSM and associated with both steatosis and body mass index, the two factors mostly affecting LSM performance in NAFLD. We aimed to determine whether prediction of liver fibrosis by LSM in NAFLD patients is affected by CAP values. Patients (n = 324) were assessed by clinical and histological (Kleiner score) features. LSM and CAP were performed using the M probe. CAP values were grouped by tertiles (lower 132‐298, middle 299‐338, higher 339‐400 dB/m). Among patients with F0‐F2 fibrosis, mean LSM values, expressed in kilopascals, increased according to CAP tertiles (6.8 versus 8.6 versus 9.4, P = 0.001), and along this line the area under the curve of LSM for the diagnosis of F3‐F4 fibrosis was progressively reduced from lower to middle and further to higher CAP tertiles (0.915, 0.848‐0.982; 0.830, 0.753‐0.908; 0.806, 0.723‐0.890). As a consequence, in subjects with F0‐F2 fibrosis, the rates of false‐positive LSM results for F3‐F4 fibrosis increased according to CAP tertiles (7.2% in lower versus 16.6% in middle versus 18.1% in higher). Consistent with this, a decisional flowchart for predicting fibrosis was suggested by combining both LSM and CAP values. Conclusions: In patients with NAFLD, CAP values should always be taken into account in order to avoid overestimations of liver fibrosis assessed by transient elastography. (Hepatology 2017;65:1145‐1155).
Purpose
In MRI, the macromolecular proton fraction (MPF) is a key parameter of magnetization transfer (MT). It represents the relative amount of immobile protons associated with semi‐solid ...macromolecules involved in MT with free water protons. We aim to quantify MPF based on spin‐lock MRI and explore its advantages over the existing MPF‐mapping methods.
Methods
In the proposed method, termed MPF quantification based on spin‐lock (MPF‐SL), off‐resonance spin‐lock is used to sensitively measure the MT effect. MPF‐SL is designed to measure a relaxation rate (Rmpfsl) that is specific to the MT effect by removing the R1ρ relaxation due to the mobile water and chemical exchange pools. A theory is derived to quantify MPF from the measured Rmpfsl. No prior knowledge of tissue relaxation parameters, including T1 or T2, is needed to quantify MPF using MPF‐SL. The proposed approach is validated with Bloch‐McConnell simulations, phantom, and in vivo liver studies at 3.0T.
Results
Both Bloch‐McConnell simulations and phantom experiments show that MPF‐SL is insensitive to variations of the mobile water pool and the chemical exchange pool. MPF‐SL is specific to the MT effect and can measure MPF reliably. In vivo liver studies show that MPF‐SL can be used to detect collagen deposition in patients with liver fibrosis.
Conclusion
A novel MPF imaging method based on spin‐lock MRI is proposed. The confounding factors are removed, and the measurement is specific to the MT effect. It holds promise for MPF‐sensitive diagnostic imaging in clinical settings.
The development of RNA sequencing (RNA-Seq) makes it possible for us to measure transcription at an unprecedented precision and throughput. However, challenges remain in understanding the source and ...distribution of the reads, modeling the transcript abundance and developing efficient computational methods. In this article, we develop a method to deal with the isoform expression estimation problem. The count of reads falling into a locus on the genome annotated with multiple isoforms is modeled as a Poisson variable. The expression of each individual isoform is estimated by solving a convex optimization problem and statistical inferences about the parameters are obtained from the posterior distribution by importance sampling. Our results show that isoform expression inference in RNA-Seq is possible by employing appropriate statistical methods. Contact: whwong@stanford.edu Supplementary information: Supplementary data are available at Bioinformatics online.
Interactions between regulatory elements are of crucial importance for the understanding of transcriptional regulation and the interpretation of disease mechanisms. Hi-C technique has been developed ...for genome-wide detection of chromatin contacts. However, unless extremely deep sequencing is performed on a very large number of input cells, which is technically limited and expensive, current Hi-C experiments do not have high enough resolution to resolve contacts between regulatory elements. Here, we develop DeepTACT, a bootstrapping deep learning model, to integrate genome sequences and chromatin accessibility data for the prediction of chromatin contacts between regulatory elements. DeepTACT can infer not only promoter-enhancer interactions, but also promoter-promoter interactions. In tests based on promoter capture Hi-C data, DeepTACT shows better performance over existing methods. DeepTACT analysis also identifies a class of hub promoters, which are correlated with transcriptional activation across cell lines, enriched in housekeeping genes, functionally related to fundamental biological processes, and capable of reflecting cell similarity. Finally, the utility of chromatin contacts in the study of human diseases is illustrated by the association of IFNA2 to coronary artery disease via an integrative analysis of GWAS data and interactions predicted by DeepTACT.
SeqMap is a tool for mapping large amount of short sequences to the genome. It is designed for finding all the places in a reference genome where each sequence may come from. This task is essential ...to the analysis of data from ultra high-throughput sequencing machines. With a carefully designed index-filtering algorithm and an efficient implementation, SeqMap can map tens of millions of short sequences to a genome of several billions of nucleotides. Multiple substitutions and insertions/deletions of the nucleotide bases in the sequences can be tolerated and therefore detected. SeqMap supports FASTA input format and various output formats, and provides command line options for tuning almost every aspect of the mapping process. A typical mapping can be done in a few hours on a desktop PC. Parallel use of SeqMap on a cluster is also very straightforward. Contact: whwong@stanford.edu
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