A genome-wide association study of Chinese and English language phenotypes in Hong Kong Chinese children.

Dyslexia and developmental language disorders are important learning difficulties. However, their genetic basis remains poorly understood, and most genetic studies were performed on Europeans. There is a lack of genome-wide association studies (GWAS) on literacy phenotypes of Chinese as a native language and English as a second language (ESL) in a Chinese population. In this study, we conducted GWAS on 34 reading/language-related phenotypes in Hong Kong Chinese bilingual children (including both twins and singletons; total N = 1046). We performed association tests at the single-variant, gene, and pathway levels. In addition, we tested genetic overlap of these phenotypes with other neuropsychiatric disorders, as well as cognitive performance (CP) and educational attainment (EA) using polygenic risk score (PRS) analysis. Totally 5 independent loci (LD-clumped at r2 = 0.01; MAF > 0.05) reached genome-wide significance (p < 5e-08; filtered by imputation quality metric Rsq>0.3 and having at least 2 correlated SNPs (r2 > 0.5) with p < 1e-3). The loci were associated with a range of language/literacy traits such as Chinese vocabulary, character and word reading, and rapid digit naming, as well as English lexical decision. Several SNPs from these loci mapped to genes that were reported to be associated with EA and other neuropsychiatric phenotypes, such as MANEA and PLXNC1. In PRS analysis, EA and CP showed the most consistent and significant polygenic overlap with a variety of language traits, especially English literacy skills. To summarize, this study revealed the genetic basis of Chinese and English abilities in a group of Chinese bilingual children. Further studies are warranted to replicate the findings.

Uncovering Clinical Risk Factors and Predicting Severe COVID-19 Cases Using UK Biobank Data: Machine Learning Approach.

BACKGROUND: COVID-19 is a major public health concern. Given the extent of the pandemic, it is urgent to identify risk factors associated with disease severity. More accurate prediction of those at risk of developing severe infections is of high clinical importance. OBJECTIVE: Based on the UK Biobank (UKBB), we aimed to build machine learning models to predict the risk of developing severe or fatal infections, and uncover major risk factors involved. METHODS: We first restricted the analysis to infected individuals (n=7846), then performed analysis at a population level, considering those with no known infection as controls (ncontrols=465,728). Hospitalization was used as a proxy for severity. A total of 97 clinical variables (collected prior to the COVID-19 outbreak) covering demographic variables, comorbidities, blood measurements (eg, hematological/liver/renal function/metabolic parameters), anthropometric measures, and other risk factors (eg, smoking/drinking) were included as predictors. We also constructed a simplified (lite) prediction model using 27 covariates that can be more easily obtained (demographic and comorbidity data). XGboost (gradient-boosted trees) was used for prediction and predictive performance was assessed by cross-validation. Variable importance was quantified by Shapley values (ShapVal), permutation importance (PermImp), and accuracy gain. Shapley dependency and interaction plots were used to evaluate the pattern of relationships between risk factors and outcomes. RESULTS: A total of 2386 severe and 477 fatal cases were identified. For analyses within infected individuals (n=7846), our prediction model achieved area under the receiving-operating characteristic curve (AUC-ROC) of 0.723 (95% CI 0.711-0.736) and 0.814 (95% CI 0.791-0.838) for severe and fatal infections, respectively. The top 5 contributing factors (sorted by ShapVal) for severity were age, number of drugs taken (cnt_tx), cystatin C (reflecting renal function), waist-to-hip ratio (WHR), and Townsend deprivation index (TDI). For mortality, the top features were age, testosterone, cnt_tx, waist circumference (WC), and red cell distribution width. For analyses involving the whole UKBB population, AUCs for severity and fatality were 0.696 (95% CI 0.684-0.708) and 0.825 (95% CI 0.802-0.848), respectively. The same top 5 risk factors were identified for both outcomes, namely, age, cnt_tx, WC, WHR, and TDI. Apart from the above, age, cystatin C, TDI, and cnt_tx were among the top 10 across all 4 analyses. Other diseases top ranked by ShapVal or PermImp were type 2 diabetes mellitus (T2DM), coronary artery disease, atrial fibrillation, and dementia, among others. For the "lite" models, predictive performances were broadly similar, with estimated AUCs of 0.716, 0.818, 0.696, and 0.830, respectively. The top ranked variables were similar to above, including age, cnt_tx, WC, sex (male), and T2DM. CONCLUSIONS: We identified numerous baseline clinical risk factors for severe/fatal infection by XGboost. For example, age, central obesity, impaired renal function, multiple comorbidities, and cardiometabolic abnormalities may predispose to poorer outcomes. The prediction models may be useful at a population level to identify those susceptible to developing severe/fatal infections, facilitating targeted prevention strategies. A risk-prediction tool is also available online. Further replications in independent cohorts are required to verify our findings.

Analysis of genetic differences between psychiatric disorders: exploring pathways and cell types/tissues involved and ability to differentiate the disorders by polygenic scores.

Although displaying genetic correlations, psychiatric disorders are clinically defined as categorical entities as they each have distinguishing clinical features and may involve different treatments. Identifying differential genetic variations between these disorders may reveal how the disorders differ biologically and help to guide more personalized treatment. Here we presented a statistical framework and comprehensive analysis to identify genetic markers differentially associated with various psychiatric disorders/traits based on GWAS summary statistics, covering 18 psychiatric traits/disorders and 26 comparisons. We also conducted comprehensive analysis to unravel the genes, pathways and SNP functional categories involved, and the cell types and tissues implicated. We also assessed how well one could distinguish between psychiatric disorders by polygenic risk scores (PRS). SNP-based heritabilities (h2snp) were significantly larger than zero for most comparisons. Based on current GWAS data, PRS have mostly modest power to distinguish between psychiatric disorders. For example, we estimated that AUC for distinguishing schizophrenia from major depressive disorder (MDD), bipolar disorder (BPD) from MDD and schizophrenia from BPD were 0.694, 0.602 and 0.618, respectively, while the maximum AUC (based on h2snp) were 0.763, 0.749 and 0.726, respectively. We also uncovered differences in each pair of studied traits in terms of their differences in genetic correlation with comorbid traits. For example, clinically defined MDD appeared to more strongly genetically correlated with other psychiatric disorders and heart disease, when compared to non-clinically defined depression in UK Biobank. Our findings highlight genetic differences between psychiatric disorders and the mechanisms involved. PRS may help differential diagnosis of selected psychiatric disorders in the future with larger GWAS samples.

A framework to decipher the genetic architecture of combinations of complex diseases: applications in cardiovascular medicine.

MOTIVATION: Currently, most genome-wide association studies (GWAS) are studies of a single disease against controls. However, an individual is often affected by more than one condition. For example, coronary artery disease (CAD) is often comorbid with type 2 diabetes mellitus (T2DM). Similarly, it is clinically meaningful to study patients with one disease but without a related comorbidity. For example, obese T2DM may have different pathophysiology from nonobese T2DM. RESULTS: We developed a statistical framework (CombGWAS) to uncover susceptibility variants for comorbid disorders (or a disorder without comorbidity), using GWAS summary statistics only. In essence, we mimicked a case-control GWAS in which the cases are affected with comorbidities or a disease without comorbidity. We extended our methodology to analyze continuous traits with clinically meaningful categories (e.g. lipids), and combination of more than two traits. We verified the feasibility and validity of our method by applying it to simulated scenarios and four cardiometabolic (CM) traits. In total, we identified 384 and 587 genomic risk loci respectively for 6 comorbidities and 12 CM disease 'subtypes' without a relevant comorbidity. Genetic correlation analysis revealed that some subtypes may be biologically distinct from others. Further Mendelian randomization analysis showed differential causal effects of different subtypes to relevant complications. For example, we found that obese T2DM is causally related to increased risk of CAD (P = 2.62E-11). AVAILABILITY AND IMPLEMENTATION: R code is available at: https://github.com/LiangyingYin/CombGWAS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The potential role of plasma fibroblast growth factor 21 as a diagnostic biomarker for abdominal aortic aneurysm presence and development.

AIMS: Fibroblast growth factor 21 (FGF21) has been identified as the master hormonal regulator of energy balance, its elevation is observed in a series of metabolic and cardiovascular diseases. Studies have implicated the role of FGF21 signaling in the pathogenesis of abdominal aortic aneurysm (AAA). We will investigate the association of FGF21 and AAA development. MATERIALS AND METHODS: In this study, we assayed plasma levels of FGF21 in 82 patients with AAA and 44 control subjects, then analyzed their relationship with clinical, biochemical and histological phenotypes. The expression of ß-klotho, an essential co-receptor of FGF21, was assessed with IHC staining and RT-qPCR. Machine learning models incorporate a combination of FGF21 and clinical data were utilized in the prediction of AAA occurrence. KEY FINDINGS: FGF21 was statistically higher in patients with AAA (781 pg/ml [533, 1213]) than in control subjects (567 pg/ml [324, 939]). After adjustment for age and BMI, we found a positive association of FGF21 levels with AAA diameters, hypertension rate and hsCRP, and a negative correlation between FGF21 levels and HDL-c. Furthermore, the protein levels of ß-klotho in abdominal aorta of AAA were found significantly lower than in control group indicating the presence of FGF21 resistance. Combining FGF21 levels with four clinical characteristics significantly improved the stratification of AAA and control groups with an AUC of 0.778. SIGNIFICANCE: Combining detection of plasma FGF21 and clinical characteristics may be reliable for identifying the presence of AAA. The role of FGF21 as a therapeutic target of AAA warrants further investigation.

Integrating Clinical Data and Imputed Transcriptome from GWAS to Uncover Complex Disease Subtypes: Applications in Psychiatry and Cardiology.

Classifying subjects into clinically and biologically homogeneous subgroups will facilitate the understanding of disease pathophysiology and development of targeted prevention and intervention strategies. Traditionally, disease subtyping is based on clinical characteristics alone, but subtypes identified by such an approach may not conform exactly to the underlying biological mechanisms. Very few studies have integrated genomic profiles (e.g., those from GWASs) with clinical symptoms for disease subtyping. Here we proposed an analytic framework capable of finding complex diseases subgroups by leveraging both GWAS-predicted gene expression levels and clinical data by a multi-view bicluster analysis. This approach connects SNPs to genes via their effects on expression, so the analysis is more biologically relevant and interpretable than a pure SNP-based analysis. Transcriptome of different tissues can also be readily modeled. We also proposed various evaluation metrics for assessing clustering performance. Our framework was able to subtype schizophrenia subjects into diverse subgroups with different prognosis and treatment response. We also applied the framework to the Northern Finland Birth Cohort (NFBC) 1966 dataset and identified high and low cardiometabolic risk subgroups in a gender-stratified analysis. The prediction strength by cross-validation was generally greater than 80%, suggesting good stability of the clustering model. Our results suggest a more data-driven and biologically informed approach to defining metabolic syndrome and subtyping psychiatric disorders. Moreover, we found that the genes "blindly" selected by the algorithm are significantly enriched for known susceptibility genes discovered in GWASs of schizophrenia or cardiovascular diseases. The proposed framework opens up an approach to subject stratification.

Leveraging genome-wide association and clinical data in revealing schizophrenia subgroups.

Schizophrenia (SCZ) has long been recognized as a highly heterogeneous disorder. Patients differed in their clinical manifestations, prognosis, and underlying pathophysiologies. Here we presented and applied a framework for finding subtypes of SCZ utilizing genome-wide association study (GWAS) and clinical data. We postulated that genetic information may help stratify patient into useful subgroups, and incorporation of other clinical information and cognitive profiles will further improve patient subtyping. We conducted cluster analysis in 387 Hong Kong Chinese with SCZ. First we performed 'single-view' clustering using genetic or clinical data alone, then proceeded to 'multi-view' clustering (MVC) accounting for both types of information. We validated clustering results by assessing subgroup differences in various outcomes. We found significant differences in outcomes including treatment response, disease course and symptom severity (Simes overall p-value using MVC = 1.64E-9). Overall speaking, we identified three subgroups with good, intermediate and poor prognosis respectively. MVC generally out-performed single-view methods. The analysis was repeated for different sets of input SNPs, and stratified analysis of male and female patients, and the results remained largely robust. We also found significant enrichment for SCZ loci among the SNPs selected by the cluster algorithm. Numerous selected genes (e.g. NRG1, ERBB4, NRXN1, ANK3) and pathways (e.g. neuregulin-ErbB4 and calcium signaling) were implicated in SCZ or related pathophysiological processes. This is first study to combine both genetic and clinical data for subtyping SCZ, and to employ genome-wide SNP data in cluster analysis of a complex disease. This work points to a new way of GWAS analysis of translational potential.

Utilizing Electronic Medical Records to Discover Changing Trends of Medical Behaviors Over Time.

OBJECTIVES: Medical behaviors are playing significant roles in the delivery of high quality and cost-effective health services. Timely discovery of changing frequencies of medical behaviors is beneficial for the improvement of health services. The main objective of this work is to discover the changing trends of medical behaviors over time. METHODS: This study proposes a two-steps approach to detect essential changing patterns of medical behaviors from Electronic Medical Records (EMRs). In detail, a probabilistic topic model, i.e., Latent Dirichlet allocation (LDA), is firstly applied to disclose yearly treatment patterns in regard to the risk stratification of patients from a large volume of EMRs. After that, the changing trends by comparing essential/critical medical behaviors in a specific time period are detected and analyzed, including changes of significant patient features with their values, and changes of critical treatment interventions with their occurring time stamps. RESULTS: We verify the effectiveness of the proposed approach on a clinical dataset containing 12,152 patient cases with a time range of 10 years. Totally, 135 patients features and 234 treatment interventions in three treatment patterns were selected to detect their changing trends. In particular, evolving trends of yearly occurring probabilities of the selected medical behaviors were categorized into six content changing patterns (i.e, 112 growing, 123 declining, 43 up-down, 16 down-up, 35 steady, and 40 jumping), using the proposed approach. Besides, changing trends of execution time of treatment interventions were classified into three occurring time changing patterns (i.e., 175 early-implemented, 50 steady-implemented and 9 delay-implemented). CONCLUSIONS: Experimental results show that our approach has an ability to utilize EMRs to discover essential evolving trends of medical behaviors, and thus provide significant potential to be further explored for health services redesign and improvement.

On local anomaly detection and analysis for clinical pathways.

OBJECTIVE: Anomaly detection, as an imperative task for clinical pathway (CP) analysis and improvement, can provide useful and actionable knowledge of interest to clinical experts to be potentially exploited. Existing studies mainly focused on the detection of global anomalous inpatient traces of CPs using the similarity measures in a structured manner, which brings order in the chaos of CPs, may decline the accuracy of similarity measure between inpatient traces, and may distort the efficiency of anomaly detection. In addition, local anomalies that exist in some subsegments of events or behaviors in inpatient traces are easily overlooked by existing approaches since they are designed for detecting global or large anomalies. METHOD: In this study, we employ a probabilistic topic model to discover underlying treatment patterns, and assume any significant unexplainable deviations from the normal behaviors surmised by the derived patterns are strongly correlated with anomalous behaviours. In this way, we can figure out the detailed local abnormal behaviors and the associations between these anomalies such that diagnostic information on local anomalies can be provided. RESULTS: The proposed approach is evaluated via a clinical data-set, including 2954 unstable angina patient traces and 483,349 clinical events, extracted from a Chinese hospital. Using the proposed method, local anomalies are detected from the log. In addition, the identified associations between the detected local anomalies are derived from the log, which lead to clinical concern on the reason resulting in these anomalies in CPs. The correctness of the proposed approach has been evaluated by three experience cardiologists of the hospital. For four types of local anomalies (i.e., unexpected events, early events, delay events, and absent events), the proposed approach achieves 94%, 71% 77%, and 93.2% in terms of recall. This is quite remarkable as we do not use a prior knowledge. CONCLUSION: Substantial experimental results show that the proposed approach can effectively detect local anomalies in CPs, and also provide diagnostic information on the detected anomalies in an informative manner.