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.

Evaluating the impact of sugar-sweetened beverages tax on overweight, obesity, and type 2 diabetes in an affluent Asian setting: A willingness-to-pay survey and simulation analysis.

BACKGROUND: The potential health effects of taxing sugar-sweetened beverages (SSBs) has been insufficiently examined in Asian contexts. This study aimed to assess the impact of SSB taxation on the prevalence of obesity/overweight and type 2 diabetes mellitus (T2DM) in Hong Kong using a willingness-to-pay (WTP) survey and simulation analysis. METHODS: A random telephone survey was conducted with 1000 adults from May to June 2020. We used a contingent valuation approach to assess individuals' WTP for SSBs under four tax payment scenarios (5%, 10%, 40%, and 50% of the current market price). Based on the WTP, a simulation analysis was conducted to project changes in SSB purchase and associated reductions in the prevalence of obesity/overweight and T2DM over a 10-year simulation period. FINDINGS: When 5% and 10% taxation rates were introduced, approximately one-third of the population were unwilling to maintain their SSB purchase. Our simulation demonstrated a gradual decline in the prevalence of obesity/overweight and diabetes with a more pronounced decrease when higher taxation rates were introduced. 10% taxation resulted in a mean reduction of 1532.7 cases of overweight/obesity per 100 thousand population at the sixth year, while T2DM prevalence decreased by 267.1 (0.3%). CONCLUSIONS: This study underscores the effects of an SSB tax on purchase behaviors and health outcomes in an affluent Asia setting, with a more pronounced influence on adult population. These findings are expected to inform policymakers in making decisions regarding an effective and equitable tax rate on SSBs.

Robust time selection for interim analysis in the Bayesian phase 2 exploratory clinical trial.

In phase 2 clinical trials, we expect to make a right Go or No-Go decision during the interim analysis (IA) and make this decision at the right time. The optimal time for IA is usually determined based on a utility function. In most previous research, utility functions aim to minimize the expected sample size or total cost in confirmatory trials. However, the selected time can vary depending on different alternative hypotheses. This paper proposes a new utility function for Bayesian phase 2 exploratory clinical trials. It evaluates the predictability and robustness of the Go and No-Go decision made during the IA. We can make a robust time selection for the IA based on the function regardless of the treatment effect assumptions.

Modelling the association between COVID-19 transmissibility and D614G substitution in SARS-CoV-2 spike protein: using the surveillance data in California as an example.

BACKGROUND: The COVID-19 pandemic poses a serious threat to global health, and pathogenic mutations are a major challenge to disease control. We developed a statistical framework to explore the association between molecular-level mutation activity of SARS-CoV-2 and population-level disease transmissibility of COVID-19. METHODS: We estimated the instantaneous transmissibility of COVID-19 by using the time-varying reproduction number (Rt). The mutation activity in SARS-CoV-2 is quantified empirically depending on (i) the prevalence of emerged amino acid substitutions and (ii) the frequency of these substitutions in the whole sequence. Using the likelihood-based approach, a statistical framework is developed to examine the association between mutation activity and Rt. We adopted the COVID-19 surveillance data in California as an example for demonstration. RESULTS: We found a significant positive association between population-level COVID-19 transmissibility and the D614G substitution on the SARS-CoV-2 spike protein. We estimate that a per 0.01 increase in the prevalence of glycine (G) on codon 614 is positively associated with a 0.49% (95% CI: 0.39 to 0.59) increase in Rt, which explains 61% of the Rt variation after accounting for the control measures. We remark that the modeling framework can be extended to study other infectious pathogens. CONCLUSIONS: Our findings show a link between the molecular-level mutation activity of SARS-CoV-2 and population-level transmission of COVID-19 to provide further evidence for a positive association between the D614G substitution and Rt. Future studies exploring the mechanism between SARS-CoV-2 mutations and COVID-19 infectivity are warranted.

Real-time quantification of the transmission advantage associated with a single mutation in pathogen genomes: a case study on the D614G substitution of SARS-CoV-2.

BACKGROUND: The COVID-19 pandemic poses serious threats to global health, and the emerging mutation in SARS-CoV-2 genomes, e.g., the D614G substitution, is one of the major challenges of disease control. Characterizing the role of the mutation activities is of importance to understand how the evolution of pathogen shapes the epidemiological outcomes at population scale. METHODS: We developed a statistical framework to reconstruct variant-specific reproduction numbers and estimate transmission advantage associated with the mutation activities marked by single substitution empirically. Using likelihood-based approach, the model is exemplified with the COVID-19 surveillance data from January 1 to June 30, 2020 in California, USA. We explore the potential of this framework to generate early warning signals for detecting transmission advantage on a real-time basis. RESULTS: The modelling framework in this study links together the mutation activity at molecular scale and COVID-19 transmissibility at population scale. We find a significant transmission advantage of COVID-19 associated with the D614G substitution, which increases the infectivity by 54% (95%CI: 36, 72). For the early alarming potentials, the analytical framework is demonstrated to detect this transmission advantage, before the mutation reaches dominance, on a real-time basis. CONCLUSIONS: We reported an evidence of transmission advantage associated with D614G substitution, and highlighted the real-time estimating potentials of modelling framework.

Long-term effectiveness of elderly health care voucher scheme strategies: a system dynamics simulation analysis.

BACKGROUND: The elderly healthcare voucher (EHCV) scheme is expected to lead to an increase in the number of elderly people selecting private primary healthcare services and reduce reliance on the public sector in Hong Kong. However, studies thus far have reported that this scheme has not received satisfactory responses. In this study, we examined changes in the ratio of visits between public and private doctors in primary care (to measure reliance on the public sector) for different strategic scenarios in the EHCV scheme. METHODS: Based on comments from an expert panel, a system dynamics model was formulated to simulate the impact of various enhanced strategies in the scheme: increasing voucher amounts, lowering the age eligibility, and designating vouchers for chronic conditions follow-up. Data and statistics for the model calibration were collected from various sources. RESULTS: The simulation results show that the current EHCV scheme is unable to reduce the utilization of public healthcare services, as well as the ratio of visits between public and private primary care among the local aging population. When comparing three different tested scenarios, even if the increase in the annual voucher amount could be maintained at the current pace or the age eligibility can be lowered to include those aged 60 years, the impact on shifts from public-to-private utilization were insignificant. The public-to-private ratio could only be marginally reduced from 0.74 to 0.64 in the first several years. Nevertheless, introducing a chronic disease-oriented voucher could result in a significant drop of 0.50 in the public-to-private ratio during the early implementation phase. However, the effect could not be maintained for an extended period. CONCLUSIONS: Our findings will assist officials in improving the design of the EHCV scheme, within the wider context of promoting primary care among the elderly. We suggest that an additional chronic disease-oriented voucher can serve as an alternative strategy. The scheme must be redesigned to address more specific objectives or provide a separate voucher that promotes under-utilized healthcare services (e.g., preventive care), instead of services designed for unspecified reasons, which may lead to concerns regarding exploitation.

Sequencing-based counting and size profiling of plasma Epstein-Barr virus DNA enhance population screening of nasopharyngeal carcinoma.

Circulating tumor-derived DNA testing for cancer screening has recently been demonstrated in a prospective study on identification of nasopharyngeal carcinoma (NPC) among 20,174 asymptomatic individuals. Plasma EBV DNA, a marker for NPC, was detected using real-time PCR. While plasma EBV DNA was persistently detectable in 97.1% of the NPCs identified, ∼5% of the general population had transiently detectable plasma EBV DNA. We hypothesized that EBV DNA in plasma of subjects with or without NPC may have different molecular characteristics. We performed target-capture sequencing of plasma EBV DNA and identified differences in the abundance and size profiles of EBV DNA molecules within plasma of NPC and non-NPC subjects. NPC patients had significantly higher amounts of plasma EBV DNA, which showed longer fragment lengths. Cutoff values were established from an exploratory dataset and tested in a validation sample set. Adopting an algorithm that required a sample to concurrently pass cutoffs for EBV DNA counting and size measurements, NPCs were detected at a positive predictive value (PPV) of 19.6%. This represented superior performance compared with the PPV of 11.0% in the prospective screening study, which required participants with an initially detectable plasma EBV DNA result to be retested within 4 weeks. The observed differences in the molecular nature of EBV DNA molecules in plasma of subjects with or without NPC were successfully translated into a sequencing-based test that had a high PPV for NPC screening and achievable through single time-point testing.

Association of technologically assisted integrated care with clinical outcomes in type 2 diabetes in Hong Kong using the prospective JADE Program: A retrospective cohort analysis.

BACKGROUND: Diabetes outcomes are influenced by host factors, settings, and care processes. We examined the association of data-driven integrated care assisted by information and communications technology (ICT) with clinical outcomes in type 2 diabetes in public and private healthcare settings. METHODS AND FINDINGS: The web-based Joint Asia Diabetes Evaluation (JADE) platform provides a protocol to guide data collection for issuing a personalized JADE report including risk categories (1-4, low-high), 5-year probabilities of cardiovascular-renal events, and trends and targets of 4 risk factors with tailored decision support. The JADE program is a prospective cohort study implemented in a naturalistic environment where patients underwent nurse-led structured evaluation (blood/urine/eye/feet) in public and private outpatient clinics and diabetes centers in Hong Kong. We retrospectively analyzed the data of 16,624 Han Chinese patients with type 2 diabetes who were enrolled in 2007-2015. In the public setting, the non-JADE group (n = 3,587) underwent structured evaluation for risk factors and complications only, while the JADE (n = 9,601) group received a JADE report with group empowerment by nurses. In a community-based, nurse-led, university-affiliated diabetes center (UDC), the JADE-Personalized (JADE-P) group (n = 3,436) received a JADE report, personalized empowerment, and annual telephone reminder for reevaluation and engagement. The primary composite outcome was time to the first occurrence of cardiovascular-renal diseases, all-site cancer, and/or death, based on hospitalization data censored on 30 June 2017. During 94,311 person-years of follow-up in 2007-2017, 7,779 primary events occurred. Compared with the JADE group (136.22 cases per 1,000 patient-years [95% CI 132.35-140.18]), the non-JADE group had higher (145.32 [95% CI 138.68-152.20]; P = 0.020) while the JADE-P group had lower event rates (70.94 [95% CI 67.12-74.91]; P < 0.001). The adjusted hazard ratios (aHRs) for the primary composite outcome were 1.22 (95% CI 1.15-1.30) and 0.70 (95% CI 0.66-0.75), respectively, independent of risk profiles, education levels, drug usage, self-care, and comorbidities at baseline. We reported consistent results in propensity-score-matched analyses and after accounting for loss to follow-up. Potential limitations include its nonrandomized design that precludes causal inference, residual confounding, and participation bias. CONCLUSIONS: ICT-assisted integrated care was associated with a reduction in clinical events, including death in type 2 diabetes in public and private healthcare settings.

Analysis of Plasma Epstein-Barr Virus DNA to Screen for Nasopharyngeal Cancer.

BACKGROUND: Circulating cell-free Epstein-Barr virus (EBV) DNA is a biomarker for nasopharyngeal carcinoma. We conducted a prospective study to investigate whether EBV DNA in plasma samples would be useful to screen for early nasopharyngeal carcinoma in asymptomatic persons. METHODS: We analyzed EBV DNA in plasma specimens to screen participants who did not have symptoms of nasopharyngeal carcinoma. Participants with initially positive results were retested approximately 4 weeks later, and those with persistently positive EBV DNA in plasma underwent nasal endoscopic examination and magnetic resonance imaging (MRI). RESULTS: A total of 20,174 participants underwent screening. EBV DNA was detectable in plasma samples obtained from 1112 participants (5.5%), and 309 (1.5% of all participants and 27.8% of those who initially tested positive) had persistently positive results on the repeated sample. Among these 309 participants, 300 underwent endoscopic examination, and 275 underwent both endoscopic examination and MRI; of these participants, 34 had nasopharyngeal carcinoma. A significantly higher proportion of participants with nasopharyngeal carcinoma that was identified by screening had stage I or II disease than in a historical cohort (71% vs. 20%, P<0.001 by the chi-square test) and had superior 3-year progression-free survival (97% vs. 70%; hazard ratio, 0.10; 95% confidence interval, 0.05 to 0.18). Nine participants declined to undergo further testing, and 1 of them presented with advanced nasopharyngeal carcinoma 32 months after enrollment. Nasopharyngeal carcinoma developed in only 1 participant with negative EBV DNA in plasma samples within 1 year after testing. The sensitivity and specificity of EBV DNA in plasma samples in screening for nasopharyngeal carcinoma were 97.1% and 98.6%, respectively. CONCLUSIONS: Analysis of EBV DNA in plasma samples was useful in screening for early asymptomatic nasopharyngeal carcinoma. Nasopharyngeal carcinoma was detected significantly earlier and outcomes were better in participants who were identified by screening than in those in a historical cohort. (Funded by the Kadoorie Charitable Foundation and the Research Grants Council of the Hong Kong government; ClinicalTrials.gov number, NCT02063399 .).

Epidemiological changes in measles infections in southern China between 2009 and 2016: a retrospective database analysis.

BACKGROUND: The incidence rate of measles in China reached a nadir in 2012 after 2 supplementary immunization activities (SIAs) were undertaken in 2009 and 2010. However, the disease began re-emerging in 2013, with a high prevalence rate observed in 2013-2014 in the southern province of Guangdong. In this study, we assessed the changes that occurred in measles epidemiology during 2009-2016, particularly between 2009 and 2011 (when the influence of the SIAs were in full effect) and between 2012 and 2016 (when this influence subsided). METHODS: Data from 22,362 patients with measles diagnosed between 2009 and 2016, and whose diagnoses were confirmed clinically and/or with laboratory testing, were extracted from the National Infectious Disease Monitoring Information System. Descriptive analyses were performed, and changes in epidemiological characteristics between 2009 and 2011 and 2012-2016 were compared. RESULTS: There was a substantial surge in 0-8-month-old patients after 2012; the incidence rate increased from 4.0 per 100,000 population in 2011 (10.3% of the total) to 280 per 100,000 population in 2013 (32.8% of the total). Patients aged 0-6 years represented 73.4% of the total increase between 2011 and 2013. Compared with 2009-2011, adults aged ≥25 years accounted for a higher proportion of patients in 2013 and after (p < 0.01), and were highest in 2016 (31% of the patient total). CONCLUSION: Despite the remarkable results achieved by SIAs in terms of providing herd immunity, the 2013 resurgence of measles revealed insufficient immunization coverage among children. Therefore routine immunization programs should be strengthened, and supplementary vaccinations targeting adults should also be contemplated.

Dexamethasone eardrop with grommet placement vs intratympanic steroid injection for sudden sensorineural hearing loss: A randomized prospective clinical trial.

OBJECTIVES: The purpose of this study was to compare different means of intratympanic steroid delivery in the treatment of idiopathic sudden sensorineural hearing loss. DESIGN: Prospective, multicentered, randomized controlled trial. SETTING AND PARTICIPANTS: Fifty-six patients who fulfilled the inclusion criteria for idiopathic sudden sensorineural hearing loss who failed or were contraindicated for oral steroids were included in this study. Patients were randomly divided into 2 groups according to delivery methods: group A received 4 sections of intratympanic dexamethasone injection and group B received grommet placement with dexamethasone delivery followed by 3 sections of dexamethasone ear drop application. Self-administered paper-based questionnaires were filled out to measure subjective pain scores, vertigo, anxiety, and overall satisfaction immediately after each procedure. Hearing threshold was measured with pure tone audiogram in the follow-up. RESULTS: There was no statistical significance detected in hearing threshold improvement between both groups (P = 0.30). Grommet placement followed by dexamethasone eardrop application demonstrated a significant difference in shorter waiting time (24 min in grommet group vs 52 min in injection group; P < 0.01); and better overall satisfaction (1.6 in grommet group vs 2.5 in injection group; P < 0.05). CONCLUSIONS: Grommet placement followed by dexamethasone eardrop application is a good alternative for a patient indicated for intratympanic steroid, with less administrative cost, shorter waiting time, and more satisfaction.

Global cytokine/chemokine profile identifies potential progression prediction indicators in hand-foot-and-mouth disease patients with Enterovirus A71 infections.

OBJECTIVE: New clinical indicators are urgently needed for predicting the progression and complications of hand-foot-and-mouth disease (HFMD) caused by EV-A71 infections. MATERIALS AND METHODS: Serum specimens from 132 EV-A71 HFMD patients and 73 health children were collected during 2012-2014 in Shenzhen, China. The specific cytokines/chemokines were detected with a 274-human cytokine antibody array, followed by a 38-inflammation cytokine array, and further validated by ELISA. RESULTS: Cytokines varied in different severity of EV-A71 HFMD patients. The ROC curve analysis revealed 5 serum cytokines with high sensitivity and specificity in predicting the disease progression. Eotaxin, IL-8 and IP-10 have showed high AUC values (0.90-0.95) for discrimination between the health controls and the patient group. The three cytokines showed high sensitivity (80-91%) and specificity (88-95%). MMP-8 had a high sensitivity and specificity to predict mild HFMD (100%, 100%). IL-1b and leptin discriminated the severe/critical group from the mild group (79% and 69% in sensitivity, 73% and 63% in specificity). CONCLUSIONS: Eotaxin, IP-10 and IL-8 could be potential indicators for predicting HFMD progression with EV-A71 infection. MMP-8 is a specific indicator for mild infection, while IL-1b and leptin display potential for predicting the severity and criticality.

Distinguishing early-stage nasopharyngeal carcinoma from benign hyperplasia using intravoxel incoherent motion diffusion-weighted MRI.

OBJECTIVES: MRI can detect early-stage nasopharyngeal carcinoma (NPC), but the detection is more challenging in early-stage NPCs because they must be distinguished from benign hyperplasia in the nasopharynx. This study aimed to determine whether intravoxel incoherent motion diffusion-weighted imaging (IVIM DWI) MRI could distinguish between these two entities. METHODS: Thirty-four subjects with early-stage NPC and 30 subjects with benign hyperplasia prospectively underwent IVIM DWI. The mean pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f) and apparent diffusion coefficient (ADC) values were calculated for all subjects and compared between the 2 groups using Student's t test. Receiver operating characteristics with the area under the curve (AUC) was used to identify the optimal threshold for all significant parameters, and the corresponding diagnostic performance was calculated. A p value of < 0.05 was considered statistically significant. RESULTS: Compared with benign hyperplasia, early-stage NPC exhibited a significantly lower D mean (0.64 ± 0.06 vs 0.87 ± 0.11 × 10-3 mm2/s), ADC0-1000 mean (0.77 ± 0.08 vs 1.00 ± 0.13 × 10-3 mm2/s), ADC300-1000 (0.63 ± 0.05 vs 0.86 ± 0.10 × 10-3 mm2/s) and a higher D* mean (32.66 ± 4.79 vs 21.96 ± 5.21 × 10-3 mm2/s) (all p < 0.001). No significant difference in the f mean was observed between the two groups (p = 0.216). The D and ADC300-1000 mean had the highest AUC of 0.985 and 0.988, respectively, and the D mean of < 0.75 × 10-3 mm2/s yielded the highest sensitivity, specificity and accuracy (100%, 93.3% and 96.9%, respectively) in distinguishing early-stage NPC from benign hyperplasia. CONCLUSION: DWI has potential to distinguish early-stage NPC from benign hyperplasia and D and ADC300-1000 mean were the most promising parameters. KEY POINTS: • Diffusion-weighted imaging has potential to distinguish early-stage nasopharyngeal carcinoma from benign hyperplasia in the nasopharynx. • The pure diffusion coefficient, pseudo-diffusion coefficient from intravoxel incoherent motion model and apparent diffusion coefficient from conventional diffusion-weighted imaging were significant parameters for distinguishing these two entities in the nasopharynx. • The pure diffusion coefficient, followed by apparent diffusion coefficient, may be the most promising parameters to be used in screening studies to help detect early-stage nasopharyngeal carcinoma.

Effects of Kinesio tape on lower limb muscle strength, hop test, and vertical jump performances: a meta-analysis.

BACKGROUND: To date, published systematic reviews concerning the effects of Kinesio Taping (KT) on muscle strength have not analysed facilitatory and inhibitory applications separately. As a result, their results could be substantially affected by clinical heterogeneity. This meta-analysis was conducted to determine the effectiveness of using a facilitatory application of KT for lower limb muscle strength and functional performance (distance in a single-leg hop and vertical jump height) in individuals without disabilities and in those with musculoskeletal conditions (muscle fatigue, chronic musculoskeletal diseases, and post-operative orthopaedic conditions). METHODS: Searches were conducted on six major electronic databases. Randomised controlled trials that used facilitatory KT were included. Standardised mean differences (SMDs) were calculated and random-effects models were used for analysis. RESULTS: Thirty-seven randomised controlled trials were included. KT was superior to controls for improving lower limb muscle strength in individuals with muscle fatigue (short-term effect, pooled SMD = 0.53, 95% CI = 0.09 to 0.96; long-term effect, pooled SMD = 0.61, 95% CI = 0.12 to 1.11) and in individuals with chronic musculoskeletal diseases (pooled SMD = 1.24, 95% CI = 0.33 to 2.16) with large effect sizes. The use of KT in populations without disabilities was not supported. There is insufficient evidence for the effect of KT on functional performance in individuals with musculoskeletal conditions. CONCLUSIONS: Contrary to prior research, the existing evidence shows that KT can improve lower limb muscle strength in individuals with muscle fatigue and chronic musculoskeletal diseases. The effect sizes produced in this meta-analysis show that KT may be superior to some existing treatments for these conditions. In addition, this study suggests that practitioners may wish to avoid the use of KT in individuals without disabilities. TRIAL REGISTRATION: PROSPERO registration number CRD42017075490 , registered on 21 November 2017.

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.

Incorporating methylation genome information improves prediction accuracy for drug treatment responses.

BACKGROUND: An accumulation of evidence has revealed the important role of epigenetic factors in explaining the etiopathogenesis of human diseases. Several empirical studies have successfully incorporated methylation data into models for disease prediction. However, it is still a challenge to integrate different types of omics data into prediction models, and the contribution of methylation information to prediction remains to be fully clarified. RESULTS: A stratified drug-response prediction model was built based on an artificial neural network to predict the change in the circulating triglyceride level after fenofibrate intervention. Associated single-nucleotide polymorphisms (SNPs), methylation of selected cytosine-phosphate-guanine (CpG) sites, age, sex, and smoking status, were included as predictors. The model with selected SNPs achieved a mean 5-fold cross-validation prediction error rate of 43.65%. After adding methylation information into the model, the error rate dropped to 41.92%. The combination of significant SNPs, CpG sites, age, sex, and smoking status, achieved the lowest prediction error rate of 41.54%. CONCLUSIONS: Compared to using SNP data only, adding methylation data in prediction models slightly improved the error rate; further prediction error reduction is achieved by a combination of genome, methylation genome, and environmental factors.

A proof-of-concept study to evaluate the efficacy and safety of BTI320 on post-prandial hyperglycaemia in Chinese subjects with pre-diabetes.

BACKGROUND: Galactomannan(s) are plant-derived fiber shown to reduce post-prandial blood glucose by delaying intestinal absorption of carbohydrates and slowing down gastric emptying. We examined glucose-lowering effects of BTI320, a propriety fractionated mannan(s) administered as a chewable tablet before meal in a proof-of-concept study in Chinese subjects with prediabetes. METHODS: Sixty Chinese adults aged 18-70 years with either impaired fasting glucose, impaired glucose tolerance, or glycated haemoglobin 5.7-6.4% (39-46 mmol/mol), were randomly assigned in 2:2:1 ratio to either BTI320 8 g (high dose), BTI320 4 g (low dose) or matching-placebo three times daily before meal for 16 weeks. The primary endpoint was change in fructosamine in subjects treated with BTI320 compared with placebo from baseline to week 4. Indices of glycaemic variability based on continuous glucose monitoring (CGM) and standard meal tolerance test were explored in secondary analyses. RESULTS: Of 60 subjects randomized, 3 subjects discontinued study treatment prematurely. In intention-to-treat analysis, no significant differences in change in serum fructosamine between low or high dose BTI320 and placebo were observed. Using random effect models, adjusted for variability by meals, treatment with low dose BTI320 was associated with reduction in 1-h (p < 0.01), 2-h (p = 0.01) and 3-h (p = 0.02) post-prandial incremental glucose area-under-curve and post-meal maximum glucose (p = 0.03) compared with placebo. Subjects receiving low dose BTI320 had greater body weight reduction than placebo group. CONCLUSIONS: BTI320 did not change fructosamine levels compared with placebo. BTI320 reduced glycaemic variability based on CGM indices. TRIAL REGISTRATION: The study was registered at www.clinicaltrials.gov , reference number NCT02358668 (9 February 2015).

A fast and powerful W-test for pairwise epistasis testing.

Epistasis plays an essential role in the development of complex diseases. Interaction methods face common challenge of seeking a balance between persistent power, model complexity, computation efficiency, and validity of identified bio-markers. We introduce a novel W-test to identify pairwise epistasis effect, which measures the distributional difference between cases and controls through a combined log odds ratio. The test is model-free, fast, and inherits a Chi-squared distribution with data adaptive degrees of freedom. No permutation is needed to obtain the P-values. Simulation studies demonstrated that the W-test is more powerful in low frequency variants environment than alternative methods, which are the Chi-squared test, logistic regression and multifactor-dimensionality reduction (MDR). In two independent real bipolar disorder genome-wide associations (GWAS) datasets, the W-test identified significant interactions pairs that can be replicated, including SLIT3-CENPN, SLIT3-TMEM132D, CNTNAP2-NDST4 and CNTCAP2-RTN4R The genes in the pairs play central roles in neurotransmission and synapse formation. A majority of the identified loci are undiscoverable by main effect and are low frequency variants. The proposed method offers a powerful alternative tool for mapping the genetic puzzle underlying complex disorders.

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.

A W-test collapsing method for rare-variant association testing in exome sequencing data.

Advancement in sequencing technology enables the study of association between complex disorder phenotypes and single-nucleotide polymorphisms with rare mutations. However, the rare genetic variant has extremely small variance and impairs testing power of traditional statistical methods. We introduce a W-test collapsing method to evaluate rare-variant association by measuring the distributional differences between cases and controls through combined log of odds ratio within a genomic region. The method is model-free and inherits chi-squared distribution with degrees of freedom estimated from bootstrapped samples of the data, and allows for fast and accurate P-value calculation without the need of permutations. The proposed method is compared with the Weighted-Sum Statistic and Sequence Kernel Association Test on simulation datasets, and showed good performances and significantly faster computing speed. In the application of real next-generation sequencing dataset of hypertensive disorder, it identified genes of interesting biological functions associated to metabolism disorder and inflammation, including the MACROD1, NLRP7, AGK, PAK6, and APBB1. The proposed method offers an efficient and effective way for testing rare genetic variants in whole exome sequencing datasets.