A Prism Vote method for individualized risk prediction of traits in genotype data of Multi-population.

Multi-population cohorts offer unprecedented opportunities for profiling disease risk in large samples, however, heterogeneous risk effects underlying complex traits across populations make integrative prediction challenging. In this study, we propose a novel Bayesian probability framework, the Prism Vote (PV), to construct risk predictions in heterogeneous genetic data. The PV views the trait of an individual as a composite risk from subpopulations, in which stratum-specific predictors can be formed in data of more homogeneous genetic structure. Since each individual is described by a composition of subpopulation memberships, the framework enables individualized risk characterization. Simulations demonstrated that the PV framework applied with alternative prediction methods significantly improved prediction accuracy in mixed and admixed populations. The advantage of PV enlarges as genetic heterogeneity and sample size increase. In two real genome-wide association data consists of multiple populations, we showed that the framework considerably enhanced prediction accuracy of the linear mixed model in five-group cross validations. The proposed method offers a new aspect to analyze individual's disease risk and improve accuracy for predicting complex traits in genotype data.

Deep learning identifies explainable reasoning paths of mechanism of action for drug repurposing from multilayer biological network.

The discovery and repurposing of drugs require a deep understanding of the mechanism of drug action (MODA). Existing computational methods mainly model MODA with the protein-protein interaction (PPI) network. However, the molecular interactions of drugs in the human body are far beyond PPIs. Additionally, the lack of interpretability of these models hinders their practicability. We propose an interpretable deep learning-based path-reasoning framework (iDPath) for drug discovery and repurposing by capturing MODA on by far the most comprehensive multilayer biological network consisting of the complex high-dimensional molecular interactions between genes, proteins and chemicals. Experiments show that iDPath outperforms state-of-the-art machine learning methods on a general drug repurposing task. Further investigations demonstrate that iDPath can identify explicit critical paths that are consistent with clinical evidence. To demonstrate the practical value of iDPath, we apply it to the identification of potential drugs for treating prostate cancer and hypertension. Results show that iDPath can discover new FDA-approved drugs. This research provides a novel interpretable artificial intelligence perspective on drug discovery.

One-year Outcomes after Discharge from Noncardiac Surgery and Association between Predischarge Complications and Death after Discharge: Analysis of the VISION Prospective Cohort Study.

BACKGROUND: In previous analyses, myocardial injury after noncardiac surgery, major bleeding, and sepsis were independently associated with most deaths in the 30 days after noncardiac surgery, but most of these deaths occurred during the index hospitalization for surgery. The authors set out to describe outcomes after discharge from hospital up to 1 yr after inpatient noncardiac surgery and associations between predischarge complications and postdischarge death up to 1 yr after surgery. METHODS: This study was an analysis of patients discharged after inpatient noncardiac surgery in a large international prospective cohort study across 28 centers from 2007 to 2013 of patients aged 45 yr or older followed to 1 yr after surgery. The study estimated (1) the cumulative postdischarge incidence of death and other outcomes up to a year after surgery and (2) the adjusted time-varying associations between postdischarge death and predischarge complications including myocardial injury after noncardiac surgery, major bleeding, sepsis, infection without sepsis, stroke, congestive heart failure, clinically important atrial fibrillation or flutter, amputation, venous thromboembolism, and acute kidney injury managed with dialysis. RESULTS: Among 38,898 patients discharged after surgery, the cumulative 1-yr incidence was 5.8% (95% CI, 5.5 to 6.0%) for all-cause death and 24.7% (95% CI, 24.2 to 25.1%) for all-cause hospital readmission. Predischarge complications were associated with 33.7% (95% CI, 27.2 to 40.2%) of deaths up to 30 days after discharge and 15.0% (95% CI, 12.0 to 17.9%) up to 1 yr. Most of the association with death was due to myocardial injury after noncardiac surgery (15.6% [95% CI, 9.3 to 21.9%] of deaths within 30 days, 6.4% [95% CI, 4.1 to 8.7%] within 1 yr), major bleeding (15.0% [95% CI, 8.3 to 21.7%] within 30 days, 4.7% [95% CI, 2.2 to 7.2%] within 1 yr), and sepsis (5.4% [95% CI, 2.2 to 8.6%] within 30 days, 2.1% [95% CI, 1.0 to 3.1%] within 1 yr). CONCLUSIONS: One in 18 patients 45 yr old or older discharged after inpatient noncardiac surgery died within 1 yr, and one quarter were readmitted to the hospital. The risk of death associated with predischarge perioperative complications persists for weeks to months after discharge.

Hypotension-Avoidance Versus Hypertension-Avoidance Strategies in Noncardiac Surgery : An International Randomized Controlled Trial.

BACKGROUND: Among patients having noncardiac surgery, perioperative hemodynamic abnormalities are associated with vascular complications. Uncertainty remains about what intraoperative blood pressure to target and how to manage long-term antihypertensive medications perioperatively. OBJECTIVE: To compare the effects of a hypotension-avoidance and a hypertension-avoidance strategy on major vascular complications after noncardiac surgery. DESIGN: Partial factorial randomized trial of 2 perioperative blood pressure management strategies (reported here) and tranexamic acid versus placebo. (ClinicalTrials.gov: NCT03505723). SETTING: 110 hospitals in 22 countries. PATIENTS: 7490 patients having noncardiac surgery who were at risk for vascular complications and were receiving 1 or more long-term antihypertensive medications. INTERVENTION: In the hypotension-avoidance strategy group, the intraoperative mean arterial pressure target was 80 mm Hg or greater; before and for 2 days after surgery, renin-angiotensin-aldosterone system inhibitors were withheld and the other long-term antihypertensive medications were administered only for systolic blood pressures 130 mm Hg or greater, following an algorithm. In the hypertension-avoidance strategy group, the intraoperative mean arterial pressure target was 60 mm Hg or greater; all antihypertensive medications were continued before and after surgery. MEASUREMENTS: The primary outcome was a composite of vascular death and nonfatal myocardial injury after noncardiac surgery, stroke, and cardiac arrest at 30 days. Outcome adjudicators were masked to treatment assignment. RESULTS: The primary outcome occurred in 520 of 3742 patients (13.9%) in the hypotension-avoidance group and in 524 of 3748 patients (14.0%) in the hypertension-avoidance group (hazard ratio, 0.99 [95% CI, 0.88 to 1.12]; P = 0.92). Results were consistent for patients who used 1 or more than 1 antihypertensive medication in the long term. LIMITATION: Adherence to the assigned strategies was suboptimal; however, results were consistent across different adherence levels. CONCLUSION: In patients having noncardiac surgery, our hypotension-avoidance and hypertension-avoidance strategies resulted in a similar incidence of major vascular complications. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research, National Health and Medical Research Council (Australia), and Research Grant Council of Hong Kong.

Population sepsis incidence, mortality, and trends in Hong Kong between 2009-2018 using clinical and administrative data.

BACKGROUND: Sepsis surveillance using electronic health record (EHR)-based data may provide more accurate epidemiologic estimates than administrative data, but experience with this approach to estimate population-level sepsis burden is lacking. METHODS: This was a retrospective cohort study including all adults admitted to publicly-funded hospitals in Hong Kong between 2009-2018. Sepsis was defined as clinical evidence of presumed infection (clinical cultures and treatment with antibiotics) and concurrent acute organ dysfunction (≥2 point increase in baseline SOFA score). Trends in incidence, mortality, and case fatality risk (CFR) were modelled by exponential regression. Performance of the EHR-based definition was compared with 4 administrative definitions using 500 medical record reviews. RESULTS: Among 13,550,168 hospital episodes during the study period, 485,057 (3.6%) had sepsis by EHR-based criteria with 21.5% CFR. In 2018, age- and sex-adjusted standardized sepsis incidence was 759 per 100,000 (relative +2.9%/year [95%CI 2.0, 3.8%] between 2009-2018) and standardized sepsis mortality was 156 per 100,000 (relative +1.9%/year [95%CI 0.9,2.9%]). Despite decreasing CFR (relative -0.5%/year [95%CI -1.0, -0.1%]), sepsis accounted for an increasing proportion of all deaths (relative +3.9%/year [95%CI 2.9, 4.9%]). Medical record reviews demonstrated that the EHR-based definition more accurately identified sepsis than administrative definitions (AUC 0.91 vs 0.52-0.55, p < 0.001). CONCLUSIONS: An objective EHR-based surveillance definition demonstrated an increase in population-level standardized sepsis incidence and mortality in Hong Kong between 2009-2018 and was much more accurate than administrative definitions. These findings demonstrate the feasibility and advantages of an EHR-based approach for widescale sepsis surveillance.

Lysosome activation in peripheral blood mononuclear cells and prognostic significance of circulating LC3B in COVID-19.

Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, causing significant mortality. There is a mechanistic relationship between intracellular coronavirus replication and deregulated autophagosome-lysosome system. We performed transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients and identified the aberrant upregulation of genes in the lysosome pathway. We further determined the capability of two circulating markers, namely microtubule-associated proteins 1A/1B light chain 3B (LC3B) and (p62/SQSTM1) p62, both of which depend on lysosome for degradation, in predicting the emergence of moderate-to-severe disease in COVID-19 patients requiring hospitalization for supplemental oxygen therapy. Logistic regression analyses showed that LC3B was associated with moderate-to-severe COVID-19, independent of age, sex and clinical risk score. A decrease in LC3B concentration <5.5 ng/ml increased the risk of oxygen and ventilatory requirement (adjusted odds ratio: 4.6; 95% CI: 1.1-22.0; P = 0.04). Serum concentrations of p62 in the moderate-to-severe group were significantly lower in patients aged 50 or below. In conclusion, lysosome function is deregulated in PBMCs isolated from COVID-19 patients, and the related biomarker LC3B may serve as a novel tool for stratifying patients with moderate-to-severe COVID-19 from those with asymptomatic or mild disease. COVID-19 patients with a decrease in LC3B concentration <5.5 ng/ml will require early hospital admission for supplemental oxygen therapy and other respiratory support.

Streptococcus thermophilus Inhibits Colorectal Tumorigenesis Through Secreting ß-Galactosidase.

BACKGROUND & AIMS: Streptococcus thermophilus was identified to be depleted in patients with colorectal cancer (CRC) by shotgun metagenomic sequencing of 526 multicohort fecal samples. Here, we aim to investigate whether this bacterium could act as a prophylactic for CRC prevention. METHODS: The antitumor effects of S thermophilus were assessed in cultured colonic epithelial cells and in 2 murine models of intestinal tumorigenesis. The tumor-suppressive protein produced by S thermophilus was identified by mass spectrometry and followed by ß-galactosidase activity assay. The mutant strain of S thermophilus was constructed by homologous recombination. The effect of S thermophilus on the gut microbiota composition was assessed by shotgun metagenomic sequencing. RESULTS: Oral gavage of S thermophilus significantly reduced tumor formation in both Apcmin/+ and azoxymethane-injected mice. Coincubation with S thermophilus or its conditioned medium decreased the proliferation of cultured CRC cells. ß-Galactosidase was identified as the critical protein produced by S thermophilus by mass spectrometry screening and ß-galactosidase activity assay. ß-Galactosidase secreted by S thermophilus inhibited cell proliferation, lowered colony formation, induced cell cycle arrest, and promoted apoptosis of cultured CRC cells and retarded the growth of CRC xenograft. The mutant S thermophilus without functional ß-galactosidase lost its tumor-suppressive effect. Also, S thermophilus increased the gut abundance of known probiotics, including Bifidobacterium and Lactobacillus via ß-galactosidase. ß-Galactosidase-dependent production of galactose interfered with energy homeostasis to activate oxidative phosphorylation and downregulate the Hippo pathway kinases, which partially mediated the anticancer effects of S thermophilus. CONCLUSION: S thermophilus is a novel prophylactic for CRC prevention in mice. The tumor-suppressive effect of S thermophilus is mediated at least by the secretion of ß-galactosidase.

Efficacy of the dual-action GA-KR12 peptide for remineralising initial enamel caries: an in vitro study.

OBJECTIVE: To investigate the antibiofilm and remineralising effects of the dual-action peptide GA-KR12 on artificial enamel caries. MATERIALS AND METHODS: Enamel blocks with artificial caries were treated with sterilised deionised water as control or GA-KR12. The blocks underwent biochemical cycling with Streptococcus mutans for 3 weeks. The architecture, viability, and growth kinetics of the biofilm were determined, respectively, by scanning electron microscopy (SEM), confocal laser scanning microscopy, and quantitative (culture colony-forming units, CFUs). The mineral loss, calcium-to-phosphorus ratio, surface morphology, and crystal characteristics of the enamel surface were determined, respectively, using micro-computed tomography, energy dispersive spectroscopy, SEM, and X-ray diffraction (XRD). RESULTS: SEM showed confluent growth of S. mutans in the control group but not in the GA-KR12-treated group. The dead-to-live ratios of the control and GA-KR12-treated groups were 0.42 ± 0.05 and 0.81 ± 0.08, respectively (p < 0.001). The log CFUs of the control and GA-KR12-treated groups were 8.15 ± 0.32 and 6.70 ± 0.49, respectively (p < 0.001). The mineral losses of the control and GA-KR12-treated groups were 1.39 ± 0.09 gcm-3 and 1.19 ± 0.05 gcm-3, respectively (p < 0.001). The calcium-to-phosphorus molar ratios of the control and GA-KR12-treated groups were 1.47 ± 0.03 and 1.57 ± 0.02, respectively (p < 0.001). A uniformly remineralised prismatic pattern on enamel blocks was observed in the GA-KR12-treated but not in the control group. The hydroxyapatite in the GA-KR12-treated group was better crystallised than that in the control group. CONCLUSION: The dual-action peptide GA-KR12 inhibited the growth of S. mutans biofilm and promoted the remineralisation of enamel caries. CLINICAL RELEVANCE: GA-KR12 potentially is applicable for managing enamel caries.

Host Cell Antimicrobial Responses against Helicobacter pylori Infection: From Biological Aspects to Therapeutic Strategies.

The colonization of Helicobacter pylori (H. pylori) in human gastric mucosa is highly associated with the occurrence of gastritis, peptic ulcer, and gastric cancer. Antibiotics, including amoxicillin, clarithromycin, furazolidone, levofloxacin, metronidazole, and tetracycline, are commonly used and considered the major treatment regimens for H. pylori eradication, which is, however, becoming less effective by the increasing prevalence of H pylori resistance. Thus, it is urgent to understand the molecular mechanisms of H. pylori pathogenesis and develop alternative therapeutic strategies. In this review, we focus on the virulence factors for H. pylori colonization and survival within host gastric mucosa and the host antimicrobial responses against H. pylori infection. Moreover, we describe the current treatments for H. pylori eradication and provide some insights into new therapeutic strategies for H. pylori infection.

Lactobacillus gallinarum modulates the gut microbiota and produces anti-cancer metabolites to protect against colorectal tumourigenesis.

OBJECTIVE: Using faecal shotgun metagenomic sequencing, we identified the depletion of Lactobacillus gallinarum in patients with colorectal cancer (CRC). We aimed to determine the potential antitumourigenic role of L. gallinarum in colorectal tumourigenesis. DESIGN: The tumor-suppressive effect of L. gallinarum was assessed in murine models of CRC. CRC cell lines and organoids derived from patients with CRC were cultured with L. gallinarum or Escherichia coli MG1655 culture-supernatant to evaluate cell proliferation, apoptosis and cell cycle distribution. Gut microbiota was assessed by 16S ribosomal DNA sequencing. Antitumour molecule produced from L. gallinarum was identified by liquid chromatography mass spectrometry (LC-MS/MS) and targeted mass spectrometry. RESULTS: L. gallinarum significantly reduced intestinal tumour number and size compared with E. coli MG1655 and phosphate-buffered saline in both male and female murine intestinal tumourigenesis models. Faecal microbial profiling revealed enrichment of probiotics and depletion of pathogenic bacteria in L. gallinarum-treated mice. Culturing CRC cells with L. gallinarum culture-supernatant (5%, 10% and 20%) concentration-dependently suppressed cell proliferation and colony formation. L. gallinarum culture-supernatant significantly promoted apoptosis in CRC cells and patient-derived CRC organoids, but not in normal colon epithelial cells. Only L. gallinarum culture-supernatant with fraction size <3 kDa suppressed proliferation in CRC cells. Using LC-MS/MS, enrichments of indole-3-lactic acid (ILA) was identified in both L. gallinarum culture-supernatant and the gut of L. gallinarum-treated mice. ILA displayed anti-CRC growth in vitro and inhibited intestinal tumourigenesis in vivo. CONCLUSION: L. gallinarum protects against intestinal tumourigenesis by producing protective metabolites that can promote apoptosis of CRC cells.

MicroRNAs in atopic dermatitis: A systematic review.

Atopic dermatitis (AD) is a chronic and recurrent inflammatory skin disease, affecting up to 10% to 20% of children and 3% of adults. Although allergen sensitization, skin barrier abnormalities and type 2 immune responses are involved, the exact molecular pathogenesis of AD remains unclear. MicroRNAs (miRNAs) are short (19-25 nucleotides) single-stranded RNA molecules that regulate gene expression at post-transcriptional level and are implicated in the pathogenesis of many inflammatory and immunological skin disorders. This systematic review sought to summarize our current understanding regarding the role of miRNAs in AD development. We searched articles indexed in PubMed (MEDLINE) and Web of Science databases using Medical Subject Heading (MeSH) or Title/Abstract words ('microRNA/miRNA' and 'atopic dermatitis/eczema') from inception through January 2020. Observational studies revealed dysregulation of miRNAs, including miR-143, miR-146a, miR-151a, miR-155 and miR-223, in AD patients. Experimental studies confirmed their functions in regulating keratinocyte proliferation/apoptosis, cytokine signalling and nuclear factor-κB-dependent inflammatory responses, together with T helper 17 and regulatory T cell activities. Altogether, this systematic review brings together contemporary findings on how deregulation of miRNAs contributes to AD.

Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer.

OBJECTIVES: Bacteriome and virome alterations are associated with colorectal cancer (CRC). Nevertheless, the gut fungal microbiota in CRC remains largely unexplored. We aimed to characterise enteric mycobiome in CRC. DESIGN: Faecal shotgun metagenomic sequences of 184 patients with CRC, 197 patients with adenoma and 204 control subjects from Hong Kong were analysed (discovery cohort: 73 patients with CRC and 92 control subjects; validation cohort: 111 patients with CRC, 197 patients with adenoma and 112 controls from Hong Kong). CRC-associated fungal markers and ecological changes were also validated in additional independent cohorts of 90 patients with CRC, 42 patients with adenoma and 66 control subjects of published repository sequences from Germany and France. Assignment of taxonomies was performed by exact k-mer alignment against an integrated microbial reference genome database. RESULTS: Principal component analysis revealed separate clusters for CRC and control (p<0.0001), with distinct mycobiomes in early-stage and late-stage CRC (p=0.0048). Basidiomycota:Ascomycota ratio was higher in CRC (p=0.0042), with increase in Malasseziomycetes (p<0.0001) and decrease in Saccharomycetes (p<0.0001) and Pneumocystidomycetes (p=0.0017). Abundances of 14 fungal biomarkers distinguished CRC from controls with an area under the receiver-operating characteristic curve (AUC) of 0.93 and validated AUCs of 0.82 and 0.74 in independent Chinese cohort V1 and European cohort V2, respectively. Further ecological analysis revealed higher numbers of co-occurring fungal intrakingdom and co-exclusive bacterial-fungal correlations in CRC (p<0.0001). Moreover, co-occurrence interactions between fungi and bacteria, mostly contributed by fungal Ascomycota and bacterial Proteobacteria in control, were reverted to co-exclusive interplay in CRC (p=0.00045). CONCLUSIONS: This study revealed CRC-associated mycobiome dysbiosis characterised by altered fungal composition and ecology, signifying that the gut mycobiome might play a role in CRC.

Alterations in Enteric Virome Are Associated With Colorectal Cancer and Survival Outcomes.

BACKGROUND & AIMS: Patients with colorectal cancer (CRC) have a different gut microbiome signature than individuals without CRC. Little is known about the viral component of CRC-associated microbiome. We aimed to identify and validate viral taxonomic markers of CRC that might be used in detection of the disease or predicting outcome. METHODS: We performed shotgun metagenomic analyses of viromes of fecal samples from 74 patients with CRC (cases) and 92 individuals without CRC (controls) in Hong Kong (discovery cohort). Viral sequences were classified by taxonomic alignment against an integrated microbial reference genome database. Viral markers associated with CRC were validated using fecal samples from 3 separate cohorts: 111 patients with CRC and 112 controls in Hong Kong, 46 patients with CRC and 63 controls in Austria, and 91 patients with CRC and 66 controls in France and Germany. Using abundance profiles of CRC-associated virome genera, we constructed random survival forest models to identify those associated with patient survival times. RESULTS: The diversity of the gut bacteriophage community was significantly increased in patients with CRC compared with controls. Twenty-two viral taxa discriminated cases from controls with an area under the receiver operating characteristic curve of 0.802 in the discovery cohort. The viral markers were validated in 3 cohorts, with area under the receiver operating characteristic curves of 0.763, 0.736, and 0.715, respectively. Clinical subgroup analysis showed that dysbiosis of the gut virome was associated with early- and late-stage CRC. A combination of 4 taxonomic markers associated with reduced survival of patients with CRC (log-rank test, P = 8.1 × 10-6) independently of tumor stage, lymph node metastases, or clinical parameters. We found altered interactions between bacteriophages and oral bacterial commensals in fecal samples from patients with CRC compared with controls. CONCLUSIONS: In a metagenomic analysis of fecal samples from patients and controls, we identified virome signatures associated with CRC. These data might be used to develop tools to identify individuals with CRC or predict outcomes.

Melatonin protected against the detrimental effects of microRNA-363 in a rat model of vitamin A-associated congenital spinal deformities: Involvement of Notch signaling.

Congenital spinal deformities are a result of defective somitogenesis and are associated with vitamin A deficiency (VAD). However, the molecular mechanisms of VAD-associated congenital spinal deformities remain largely unknown. Increasing number of studies suggested that microRNAs and melatonin played important roles in the development of congenital spinal deformities. In this study, we showed that the whole-embryo expression of miR-363 was upregulated in VAD rats. Furthermore, we demonstrated that miR-363 inhibited the proliferation and neuronal differentiation of primary cultured NSCs, accompanied by downregulation of Notch1. To this end, melatonin suppressed miR-363 expression and rescued the effects of miR-363 on NSC proliferation and neuronal differentiation together with restoration of Notch signaling. The present study provided new insights into the mechanism of VAD-associated spinal deformities and the therapeutic effect of melatonin that may lead to novel understanding of the molecular mechanisms of congenital spinal deformities.

A Zoom-Focus algorithm (ZFA) to locate the optimal testing region for rare variant association tests.

MOTIVATION: Increasing amounts of whole exome or genome sequencing data present the challenge of analysing rare variants with extremely small minor allele frequencies. Various statistical tests have been proposed, which are specifically configured to increase power for rare variants by conducting the test within a certain bin, such as a gene or a pathway. However, a gene may contain from several to thousands of markers, and not all of them are related to the phenotype. Combining functional and non-functional variants in an arbitrary genomic region could impair the testing power. RESULTS: We propose a Zoom-Focus algorithm (ZFA) to locate the optimal testing region within a given genomic region. It can be applied as a wrapper function in existing rare variant association tests to increase testing power. The algorithm consists of two steps. In the first step, Zooming, a given genomic region is partitioned by an order of two, and the best partition is located. In the second step, Focusing, the boundaries of the zoomed region are refined. Simulation studies showed that ZFA substantially increased the statistical power of rare variants' tests, including the SKAT, SKAT-O, burden test and the W-test. The algorithm was applied on real exome sequencing data of hypertensive disorder, and identified biologically relevant genetic markers to metabolic disorders that were undetectable by a gene-based method. The proposed algorithm is an efficient and powerful tool to enhance the power of association study for whole exome or genome sequencing data. AVAILABILITY AND IMPLEMENTATION: The ZFA software is available at: http://www2.ccrb.cuhk.edu.hk/statgene/software.html. CONTACT: maggiew@cuhk.edu.hk or bzee@cuhk.edu.hk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer.

OBJECTIVE: To evaluate the potential for diagnosing colorectal cancer (CRC) from faecal metagenomes. DESIGN: We performed metagenome-wide association studies on faecal samples from 74 patients with CRC and 54 controls from China, and validated the results in 16 patients and 24 controls from Denmark. We further validated the biomarkers in two published cohorts from France and Austria. Finally, we employed targeted quantitative PCR (qPCR) assays to evaluate diagnostic potential of selected biomarkers in an independent Chinese cohort of 47 patients and 109 controls. RESULTS: Besides confirming known associations of Fusobacterium nucleatum and Peptostreptococcus stomatis with CRC, we found significant associations with several species, including Parvimonas micra and Solobacterium moorei. We identified 20 microbial gene markers that differentiated CRC and control microbiomes, and validated 4 markers in the Danish cohort. In the French and Austrian cohorts, these four genes distinguished CRC metagenomes from controls with areas under the receiver-operating curve (AUC) of 0.72 and 0.77, respectively. qPCR measurements of two of these genes accurately classified patients with CRC in the independent Chinese cohort with AUC=0.84 and OR of 23. These genes were enriched in early-stage (I-II) patient microbiomes, highlighting the potential for using faecal metagenomic biomarkers for early diagnosis of CRC. CONCLUSIONS: We present the first metagenomic profiling study of CRC faecal microbiomes to discover and validate microbial biomarkers in ethnically different cohorts, and to independently validate selected biomarkers using an affordable clinically relevant technology. Our study thus takes a step further towards affordable non-invasive early diagnostic biomarkers for CRC from faecal samples.

Stratified polygenic risk prediction model with application to CAGI bipolar disorder sequencing data.

Genetic data consists of a wide range of marker types, including common, low-frequency, and rare variants. Multiple genetic markers and their interactions play central roles in the heritability of complex disease. In this study, we propose an algorithm that uses a stratified variable selection design by genetic architectures and interaction effects, achieved by a dataset-adaptive W-test. The polygenic sets in all strata were integrated to form a classification rule. The algorithm was applied to the Critical Assessment of Genome Interpretation 4 bipolar challenge sequencing data. The prediction accuracy was 60% using genetic markers on an independent test set. We found that epistasis among common genetic variants contributed most substantially to prediction precision. However, the sample size was not large enough to draw conclusions for the lack of predictability of low-frequency variants and their epistasis.

HULC: an oncogenic long non-coding RNA in human cancer.

Highly up-regulated in liver cancer (HULC) was originally identified as the most overexpressed long non-coding RNA in hepatocellular carcinoma. Since its discovery, the aberrant up-regulation of HULC has been demonstrated in other cancer types, including gastric cancer, pancreatic cancer, osteosarcoma and hepatic metastasis of colorectal cancer. Recent discoveries have also shed new light on the upstream molecular mechanisms underlying HULC deregulation. As an oncogene, HULC promotes tumorigenesis by regulating multiple pathways, such as down-regulation of EEF1E1, promotion of abnormal lipid metabolism, and up-regulation of sphingosine kinase 1. Pertinent to clinical practice, a genetic variant in the HULC gene has been found to alter the risk for hepatocellular carcinoma and oesophageal cancer, whereas cancer patients with high or low expression of HULC exhibit different clinical outcome. These findings highlighted the pathogenic role and clinical utility of HULC in human cancers. Further efforts are warranted to promote the development of HULC-directed therapeutics.

MicroRNA-379 suppresses osteosarcoma progression by targeting PDK1.

Osteosarcoma is the most common primary bone tumour. Increasing evidence has demonstrated the pathogenic role of microRNA (miRNAs) dysregulation in tumour development. miR-379 was previously reported to function as an oncogenic or tumour-suppressing miRNA in a tissue-dependent manner. However, its function in osteosarcoma remains unknown. In this study, we found that the expression of miR-379 was downregulated in osteosarcoma tissues and cell lines. Further functional characterization revealed that miR-379 suppressed osteosarcoma cell proliferation and invasion in vitro and retarded the growth of osteosarcoma xenografts in vivo. Mechanistically, PDK1 was identified as the direct target of miR-379 in osteosarcoma, in which PDK1 expression was up-regulated and showed inverse correlation with miR-379. Enforced expression of PDK1 promoted osteosarcoma cell proliferation and rescued the anti-proliferative effect of miR-379. These data suggest that miR-379 could function as a tumour-suppressing miRNA via targeting PDK1 in osteosarcoma.