Building an optimal predictive model for imputing tissue-specific gene expression by combining genotype and whole-blood transcriptome data.

Accurate imputation of tissue-specific gene expression can be a powerful tool for understanding the biological mechanisms underlying human complex traits. Existing imputation methods can be grouped into two categories according to the types of predictors used. The first category uses genotype data, while the second category uses whole-blood expression data. Both data types can be easily collected from blood, avoiding invasive tissue biopsies. In this study, we attempted to build an optimal predictive model for imputing tissue-specific gene expression by combining the genotype and whole-blood expression data. We first evaluated the imputation performance of each standalone model (using genotype data [GEN model] and using whole-blood expression data [WBE model]) using their respective data types across 47 human tissues. The WBE model outperformed the GEN model in most tissues by a large gain. Then, we developed several combined models that leverage both types of predictors to further improve imputation performance. We tried various strategies, including utilizing a merged dataset of the two data types (MERGED models) and integrating the imputation outcomes of the two standalone models (inverse variance-weighted [IVW] models). We found that one of the MERGED models noticeably outperformed the standalone models. This model involved a fixed ratio between the two regularization penalty factors for the two predictor types so that the contribution of the whole-blood transcriptome is upweighted compared with the genotype. Our study suggests that one can improve the imputation of tissue-specific gene expression by combining the genotype and whole-blood expression, but the improvement can be largely dependent on the combination strategy chosen.

The Relationship between Nutrient Intake and Cataracts in the Older Adult Population of Korea.

Cataracts are a prevalent ophthalmic disease worldwide, and research on the risk factors for cataracts occurrence is actively being conducted. This study aimed to investigate the relationship between nutrient intake and cataracts in the older adult population in Korea. We analyzed data from Korean adults over the age of 60 years (cataract: 2137, non-cataract: 3497) using the Korean National Health and Nutrition Examination Survey. We performed univariate simple and multiple logistic regressions, adjusting for socio-demographic, medical history, and lifestyle, to identify the associations between nutrient intake and cataracts. A higher intake of vitamin B1 in the male group was associated with a lower incidence of cataracts. A lower intake of polyunsaturated fatty acids and vitamin A, and a higher intake of vitamin B2 in the female group were associated with a higher incidence of cataracts. Our study demonstrated that polyunsaturated fatty acids, vitamin A, and vitamin B2 could affect the incidence of cataracts according to sex. The findings could be used to control nutrient intake for cataract prevention.

Phenome-wide association study of the major histocompatibility complex region in the Korean population identifies novel association signals.

Human leukocyte antigen (HLA) gene variants in the major histocompatibility complex (MHC) region are associated with numerous complex human diseases and quantitative traits. Previous phenome-wide association studies (PheWAS) for this region demonstrated that HLA association patterns to the phenome have both population-specific and population-shared components. We performed MHC PheWAS in the Korean population by analyzing associations between phenotypes and genetic variants in the MHC region using the Korea Biobank Array project data samples from the Korean Genome and Epidemiology Study cohorts. Using this single-population dataset, we curated and analyzed 82 phenotypes for 125 673 Korean individuals after imputing HLA using CookHLA, a recently developed imputation framework. More than one-third of these phenotypes showed significant associations, confirming 56 known associations and discovering 13 novel association signals that were not reported previously. In addition, we analyzed heritability explained by the variants in the MHC region and genetic correlations among phenotypes based on the MHC variants.

Acetaminophen-induced anaphylaxis: a case report

Acetaminophen is known to be generally safe, and the occurrence of anaphylaxis due to acetaminophen has been rarely reported. We report a case of acetaminopheninduced anaphylaxis in a healthy male subject who participated in a clinical trial on the pharmacokinetics of ibandronate. The subject had not experienced an allergic reaction to acetaminophen prior to this incident. The patient received 1300 mg oral acetaminophen at about 12 hours after receiving 150 mg ibandronate. After about 10 minutes, the subject developed whole-body urticaria and hypotension. The temporal association suggested that the anaphylaxis was due to acetaminophen and not ibandronate. Anaphylaxis could occur due to acetaminophen even in the absence of allergic reactions in the first dosing.

Serial optical coherence microscopy for label-free volumetric histopathology.

The observation of histopathology using optical microscope is an essential procedure for examination of tissue biopsies or surgically excised specimens in biological and clinical laboratories. However, slide-based microscopic pathology is not suitable for visualizing the large-scale tissue and native 3D organ structure due to its sampling limitation and shallow imaging depth. Here, we demonstrate serial optical coherence microscopy (SOCM) technique that offers label-free, high-throughput, and large-volume imaging of ex vivo mouse organs. A 3D histopathology of whole mouse brain and kidney including blood vessel structure is reconstructed by deep tissue optical imaging in serial sectioning techniques. Our results demonstrate that SOCM has unique advantages as it can visualize both native 3D structures and quantitative regional volume without introduction of any contrast agents.

Hydrogen Sensing Performance of ZnO Schottky Diodes in Humid Ambient Conditions with PMMA Membrane Layer.

Enhanced hydrogen sensing performance of Pt Schottky diodes on ZnO single crystal wafers in humid ambient conditions is reported using a polymethylmethacrylate (PMMA) membrane layer. ZnO diode sensors showed little change in forward current when switching to wet ambient H2 conditions with 100% relative humidity. This sensitivity drop in the presence of water vapor can be attributed to surface coverage of hydroxyl groups on the Pt surface in humid ambient conditions. The hydrogen sensitivity of PMMA-coated diode sensors recovered up to 805% in wet H2 ambient conditions at room temperature. The PMMA layer can selectively filter water vapor and allow H2 molecules to pass through the membrane layer. It is clear that the PMMA layer can effectively serve as a moisture barrier because of low water vapor permeability and its hydrophobicity. In both dry and wet conditions, ZnO diodes exhibited relatively fast and stable on/off switching in each cycle with good repeatability.

Validation of “sasLM,” an R package for linear models with type III sum of squares

The general linear model (GLM) describes the dependent variable as a linear combination of independent variables and an error term. The GLM procedure of SAS® and the “car” package in R calculate the type I, II, or III ANOVA (analysis of variance) tables. In this study, we validated the newly-developed R package, “sasLM,” which is compatible with the GLM procedure of SAS®. The “sasLM” package was validated by comparing the output with SAS®, which is the current gold standard for statistical programming. Data from ten books and articles were used for validation. The results of the “sasLM” and “car” packages were compared with those in SAS® using 194 models. All of the results in “sasLM” were identical to those of SAS®, whereas more than 20 models in “car” showed different results from those of SAS®. As the results of the “sasLM” package were similar to those in SAS® PROC GLM, the “sasLM” package could be a viable alternative method for calculating the type II and III sum of squares. The newly-developed “sasLM” package is free and open-source, therefore it can be used to develop other useful packages as well. We hope that the “sasLM” package will enable researchers to conveniently analyze linear models.

Quantitative assessment of regional variation in tissue clearing efficiency using optical coherence tomography (OCT) and magnetic resonance imaging (MRI): A feasibility study.

Tissue clearing has gained attention as a pioneering research tool for imaging of large tissue samples. This technique improves light transmission by reducing light scattering within tissues, either by removing lipids or by replacing water with a high refractive index solution. Although various clearing techniques have been developed, quantitative assessments on clearing efficacy depending on tissue properties are rare. In this study, we developed the quantitative mapping of regional clearing efficacy using mean free path in optical coherence tomography (OCT) and proton density in magnetic resonance imaging (MRI), and demonstrated its feasibility in the brain sample with four representative clearing techniques (benzyl alcohol and benzyl benzoate [BABB], ClearT, Scale, and passive CLARITY technique [PACT]). BABB (solvent-based clearing), involving both refractive index matching and lipid removal, exhibited best optical clearing performance with the highest proton density reduction both in gray and white matter. Lipid-removing techniques such as Scale (aqueous hyperhydration) and PACT (hydrogel embedding) showed higher clearing efficiency in white matter than gray matter in accordance with larger proton density increase in white matter. For ClearT (aqueous-based simple immersion), we observed lowest clearing efficiency in the white matter as well as poor lipid removal reflected in low proton density reduction. Our results showed the feasibility of the regional mapping of clearing efficacy and correlating optical transparency and proton density changes using OCT and MRI from existing tissue clearing techniques. This novel quantitative mapping of clearing efficacy depending on tissue types and clearing methods may be helpful in the development of optimized clearing methods for different biological samples.

Pharmacokinetic characteristics of fluticasone, salmeterol and tiotropium after concurrent inhalation

Chronic obstructive pulmonary disease (COPD) is a type of progressive, obstructive lung disease characterized by long-term poor airflow. The symptoms of COPD may be relieved and its progression delayed by fluticasone (FTS), salmeterol (SM), and tiotropium (TTP). The aim of this study is to investigate pharmacokinetic (PK) characteristics of inhaled FTS, SM, and TTP after co-administration. An open-label, single-arm, three-period, simple ascending dose study was conducted in 10 healthy male subjects. A single dose of FTS/SM (250/50 µg) and TTP (18 µg) were concomitantly inhaled in period 1, and the dose of each drug was escalated to two- and three-fold in periods 2 and 3, respectively, with a 2-week washout between periods. Activated charcoal was co-administered before and after inhalation to block gastrointestinal absorption. Blood samples for PK analysis were collected up to 24 hours. PK parameters were obtained by non-compartmental analysis. FTS, SM, and TTP rapidly reached maximum plasma concentration after inhalation (0.08–3.00 h, 0.03–0.10 h and 0.03–0.10 h, respectively) and were eliminated with mean half-lives of 9.29–10.44 h, 6.09–12.39 h and 0.25–47.42 h, respectively. PK assessment of the lowest dose of TTP was limited due to relatively low systemic exposure compared to the lower limit of quantification. In conclusion, PK characteristics of FTS, SM, and TTP by pulmonary absorption were evaluated after concurrent inhalation. FTS and SM showed dose-proportional PK profiles between 250–750 µg and 50–150 µg, respectively, while TTP presented dose-proportionality in the early phase exposure between 18-54 µg.

A Study on Practitioner's Perceptions on Early Screening of Autism Spectrum Disorder

OBJECTIVES: The purpose of this study is to investigate the professional knowledge and perceptions of the early screening of Autism Spectrum Disorder (ASD) in practitioners who have contact with patients with ASD. METHODS: A survey was carried out among 674 practitioners in total, where practitioners are defined as those who work at primary medical centers, public institutions, educational institutions and treatment institutions. The survey was carried out both online and offline, and it mainly focused on 1) knowledge about ASD symptoms, 2) knowledge about the early screening of ASD, 3) measures taken after ASD detection, 4) thoughts on the development of early screening tools for ASD, and 5) the current status of ASD treatment. The data collected were analyzed through descriptive statistics, analysis of frequency and cross tabulation analysis using SPSS WIN 22.0. RESULTS: The results of this study suggest that the practitioners were not aware of the exact symptoms of ASD and their professional knowledge and the environment for early screening were insufficient. Furthermore, very few and inappropriate measures were taken after the detection of ASD. In addition, there was a high demand for early ASD screening tools to be used on site and, regarding treatment, the significance of the implementation of evidence based treatments as well as the continuity of relevant research came to the fore. CONCLUSION: It seems that there is a lack of knowledge and perception of the early screening of ASD and that education and training among practitioners is urgently required. This issue is discussed in more detail in the paper.

Reliability and validity of Korean version of modified: Yale preoperative anxiety scale.

PURPOSE: The modified Yale Preoperative Anxiety Scale (mYPAS) was developed for evaluating the level of preoperative anxiety in children. The purpose of this study was to develop a Korean version of the mYPAS (K-mYPAS) and to establish its validity and reliability based on the Korean preoperative pediatric patients. METHODS: K-mYPAS was made through stringent back-translation procedure. Total enrolled 102 patients answered questionnaires of Korean version of State-Trait Anxiety Inventory for Children (K-STAIC), and were videotaped for 2 to 5 minutes before induction of anesthesia. Three observers of experienced psychiatrist, surgeon, and nurse analyzed videotape with K-mYPAS comparing to K-STAIC. The inter- and intraobservers reliability, concurrent and construct validity, sensitivity, specificity, and predictive value were analyzed. RESULTS: The value of Cronbach α for interobservers reliability was 0.939 and intraobserver reliability was statistically significant (P < 0.001). Concurrent and construct validity were also statistically significant (P < 0.001 and P < 0.001, respectively). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 81.3%, 91.4%, 81.3%, 91.4%, and 88.2%, respectively. CONCLUSION: The K-mYPAS had good psychometric properties and can be used as a reliable and valid instrument for the assessment of preoperative anxiety in children.

Wide-field optical coherence microscopy of the mouse brain slice.

The imaging capability of optical coherence microscopy (OCM) has great potential to be used in neuroscience research because it is able to visualize anatomic features of brain tissue without labeling or external contrast agents. However, the field of view of OCM is still narrow, which dilutes the strength of OCM and limits its application. In this study, we present fully automated wide-field OCM for mosaic imaging of sliced mouse brains. A total of 308 segmented OCM images were acquired, stitched, and reconstructed as an en-face brain image after intensive imaging processing. The overall imaging area was 11.2×7.0 mm (horizontal×vertical), and the corresponding pixel resolution was 1.2×1.2 µm. OCM images were compared to traditional histology stained with Nissl and Luxol fast blue (LFB). In particular, the orientation of the fibers was analyzed and quantified in wide-field OCM.

A Validation Study of the Korean Version of Social Communication Questionnaire

OBJECTIVES: The purposes of this study were to examine the reliability and validity of the Korean version of Social Communication Questionnaire (K-SCQ) and to determine cut-off scores for diagnosis of autism spectrum disorder (ASD). METHODS: A total of 166 subjects with ASD and their 186 unaffected siblings were recruited through child psychiatry clinics of university hospitals. Board certified child psychiatrists screened all probands suspected to have ASD based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. To confirm the diagnoses, the Korean versions of the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised (K-ADI-R) were administered to all the subjects. All parents completed the K-SCQ and Social Responsiveness Scale (SRS). The non-ASD siblings were evaluated with the same instruments as the probands with ASD. We performed a factor analysis to examine the structure of K-SCQ. For testing the validity of K-SCQ, we compared the difference in Lifetime and Current scores of probands with ASD and their non-ASD siblings using t-test and analysis of covariance. Correlations between the K-SCQ and other measurements of ASD symptomatology, including K-ADI-R totals and domain scores and SRS, were examined. Receiver operation characteristic curve analysis was performed to extract cutoff scores discriminating affection status. RESULTS: Four factors were extracted through factor analysis of K-SCQ ; 1) social relation and play, 2) stereotyped behavior, 3) social behavior, and 4) abnormal language. Cronbach's internal consistency was .95 in K-SCQ Lifetime, and .93 in K-SCQ Current. There were significant differences in total score of K-SCQ, both in Lifetime and Current between the ASD group and non-ASD siblings group (p<.001). K-SCQ scores were significantly correlated with K-ADI-R subdomain scores and SRS total scores (p<.001). The best-estimate cut-off scores of K-SCQ for diagnosis of ASD were 12 for 48 months and over, and 10 for below 47 months. CONCLUSION: Our findings suggest that the K-SCQ is a reliable and valid instrument for screening autistic symptoms in the Korean population. Lower cut-off scores than the original English version might be considered when using it as a screening instrument of ASD.

Association between the GRM7 rs3792452 polymorphism and attention deficit hyperacitiveity disorder in a Korean sample.

BACKGROUND: The purpose of this study was to investigate the association between the ionotropic and glutamate receptors, N-methyl D-asparate 2A (GRIN2A) and 2B (GRIN2B), and the metabotropic glutamate receptor mGluR7 (GRM7) gene polymorphisms and attention-deficit hyperactivity disorder (ADHD) in Korean population. METHODS: We conducted a case-control analysis of 202 ADHD subjects and 159 controls, performed a transmission disequilibrium test (TDT) on 149 trios, and compared scores from the continuous performance test (CPT), the Children's Depression Inventory (CDI), and the State-Trait Anxiety Inventory for Children (STAIC) according to the genotype of the glutamate receptor genes. RESULTS: There were no significant differences in the genotype or allele frequencies of the GRIN2A rs8049651, GRIN2B rs2284411, or GRM7 rs37952452 polymorphisms between the ADHD and control groups. For 148 ADHD trios, the TDT analysis also showed no preferential transmission of the GRIN2A rs8049651 or GRIN2B rs2284411 polymorphisms. However, the TDT analysis of the GRM7 rs3792452 polymorphism showed biased transmission of the G allele (χ2 = 4.67, p = 0.031). In the ADHD probands, the subjects with GG genotype in the GRM7 rs37952452 polymorphism had higher mean T-scores for omission errors on the CPT than did those with the GA or AA genotype (t = 3.38, p = 0.001). In addition, the ADHD subjects who were homozygous for the G allele in the GRM7 rs37952452 polymorphism had higher STAIC-T (t = 5.52, p < 0.001) and STAIC-S (t = 2.74, p = 0.007) scores than did those with the GA or AA genotype. CONCLUSIONS: These results provide preliminary evidence of an association between the GRM7 rs37952452 polymorphism and selective attention deficit and anxiety found within the Korean ADHD population.

Effect of ADRA2A and BDNF gene-gene interaction on the continuous performance test phenotype.

Complex phenotypes such as performance on the continuous performance test (CPT) are likely to exhibit epistasis. Genetic polymorphisms of noradrenergic system and brain-derived neurotrophic factor (BDNF), which participates in the differentiation and survival of noradrenergic neurons, have been reported to be associated with the performance on CPT. We evaluated the effect of the adrenergic α-2A receptor (ADRA2A) and BDNF gene-gene interaction on performance on the CPT in a Korean population with attention-deficit/hyperactivity disorder. In all, 122 participants with attention-deficit/hyperactivity disorder (8.6±2.3 years, 104 boys and 18 girls) completed the CPT. The DraI polymorphism of ADRA2A (rs583668) and rs11030101 polymorphism of BDNF were genotyped. Significant interaction effect was found of ADRA2A rs553668 and BDNF rs11030101 on response time variability (P=0.011) of the CPT. Our study provides preliminary evidence for the effect of the BDNF and ADRA2A gene-gene interaction on performance on the CPT in attention-deficit/hyperactivity disorder.

Neurotrophin-3 gene, intelligence, and selective attention deficit in a Korean sample with attention-deficit/hyperactivity disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder with a strong genetic component. Neurotrophin-3 (NTF3), which participates in the differentiation and survival of dopaminergic and noradrenergic neurons, has been identified as a factor in the development of ADHD. We investigated the relationships between ADHD and NTF3 gene polymorphism. METHODS: We conducted a case-control analysis of 202 ADHD subjects and 159 controls, performed a transmission disequilibrium test (TDT) on 151 trios, and compared the intelligence quotient (IQ) and a continuous performance test (CPT) according to the genotype of two single-nucleotide polymorphisms (SNPs) (rs6332 and rs6489630) in the NTF3 gene. RESULTS: In the case-control and family-based analyses, NTF3 was not significantly associated with ADHD. However, in the ADHD probands, the subjects with AA genotype in the rs6332 SNP had significantly higher mean T-scores for commission errors on the CPT than did those with the AG genotypes (p=0.045). The mean IQ of the ADHD probands who had the CC genotype of the rs6489630 SNP were higher compared with those who had the CT or TT genotype (p=0.035). The mean T-score for response time on the CPT was higher in the subjects with TT genotype in the rs6489630 SNP compared to those with the CC or CT genotype, even after adjusting for the effect of IQ (p=0.021). CONCLUSIONS: These results provide preliminary evidence of an association between NTF3 and the intelligence and selective attention deficit in the Korean population.

Gender-specific association of the brain-derived neurotrophic factor gene with attention-deficit/hyperactivity disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder with a strong genetic component. Brain-derived neurotrophic factor (BDNF), which participates in the differentiation and survival of dopaminergic and noradrenergic neurons, could play a role in ADHD development. We aimed to explore the relationships between ADHD and BDNF gene polymorphism. METHODS: We conducted a case-control analysis of 202 ADHD subjects and 159 controls, performed a transmission disequilibrium test on 151 trios, and compared the results of a continuous performance test (CPT) according to the genotype of the three single nucleotide polymorphisms (rs11030101, rs6265, rs16917204) in the BDNF gene. RESULTS: In the case-control analysis, the AA genotype of the BDNF rs11030101 polymorphism was significantly associated with ADHD only in girls (p=0.024, odds ratio=3.00). The T-G-G haplotype was significantly less frequent (p=0.005) and A-G-G was more frequent (p=0.048) in girls with ADHD than in control girls (global p=0.027). A multivariate analysis of variance for commission errors on the CPT showed a significant main effect for the rs11030101 genotype (p=0.026) and an interaction effect of the rs11030101 genotype and gender (p=0.032) in ADHD probands. CONCLUSION: These results provide preliminary evidence for a gender-specific association between BDNF and ADHD in the Korean population.

Temperament and character among Korean children and adolescents with anxiety disorders.

The purpose of this study was to evaluate the temperament and character of children and adolescents with anxiety disorders in samples from Korean community. The study subjects were children and adolescents diagnosed with social phobia (n = 66), separation anxiety disorder (n = 47), specific phobia (n = 415), and obsessive-compulsive disorder (n = 42) with the diagnostic interview schedule for children, version IV (DISC-IV) in representative community samples. Among these, we excluded other psychiatric disorder comorbid samples, with the exception of externalizing disorders. We assessed the subjects of each anxiety group using the junior temperament and character inventory (JTCI). Social phobias were significantly associated with high harm avoidance and low self-directedness on the JTCI. The association of specific phobias with high harm avoidance, and obsessive-compulsive disorder with low self-directedness was also significant. Separation anxiety disorder was not associated with any temperament and character on the JTCI. Children and adolescents with anxiety disorders have different temperaments and character profiles in accordance with diagnostic groups, which implies the specific pathophysiological mechanism of each anxiety disorder.

The Vascular Pedicle Width seen on Chest PA in Normal Korean Adults

PURPOSE: We wanted to measure the vascular pedicle width (VPW) in normal Korean adults and correlate the VPW with the body physique and we also wanted to establish the index for normal VPWs, which could be utilized in reading chest PAs. MATERIALS AND METHODS: The VPW was measured on the posteroanterior (PA) chest radiographs of 262 normal Korean adults (134 men and 128 women, age range: 22-88 years, mean age: 45.2 years), who visited the hospital for a general health examination. The relationship between the VPW and the height and the Body Mass Index (BMI) was evaluated. Correlations between height and the thoracic spine length (TSL) and between the BMI and the lateral chest wall thickness (CWT) were analyzed as well. RESULTS: The mean VPW was 47.4 (+/-6.4) mm. The VPW was positively correlated with the height (p<0.01) and the BMI (p<0.01) of the subject. The patient's height was well correlated with the TSL, and the BMI was correlated with the CWT (r=0.75, r=0.76). The table for the normal VPWs according to patient's TSL and CWT was established. CONCLUSION: By measuring the TSL and the CWT on chest PA, which reflect the height and BMI, respectively, and by utilizing the provided table for the normal VPW, we can determine the normality of a patient's VPW.