Pathway‐Guided Identification of Gene‐Gene Interactions

Assessing gene‐gene interactions (GxG) at the gene level can permit examination of epistasis at biologically functional units with amplified interaction signals from marker‐marker pairs. While current gene‐based GxG methods tend to be designed for two or a few genes, for complex traits, it is often common to have a list of many candidate genes to explore GxG. We propose a regression model with pathway‐guided regularization for detecting interactions among genes. Specifically, we use the principal components to summarize the SNP‐SNP interactions between a gene pair, and use an L1 penalty that incorporates adaptive weights based on biological guidance and trait supervision to identify important main and interaction effects. Our approach aims to combine biological guidance and data adaptiveness, and yields credible findings that may be likely to shed insights in order to formulate biological hypotheses for further molecular studies. The proposed approach can be used to explore the GxG with a list of many candidate genes and is applicable even when sample size is smaller than the number of predictors studied. We evaluate the utility of the proposed method using simulation and real data analysis. The results suggest improved performance over methods not utilizing pathway and trait guidance.     

Prioritizing Disease‐Linked Variants,Genes, and Pathways with an Interactive Whole‐Genome Analysis Pipeline

Whole‐genome sequencing (WGS) studies are uncovering disease‐associated variants in both rare and nonrare diseases. Utilizing the next‐generation sequencing for WGS requires a series of computational methods for alignment, variant detection, and annotation, and the accuracy and reproducibility of annotation results are essential for clinical implementation. However, annotating WGS with up to date genomic information is still challenging for biomedical researchers. Here, we present one of the fastest and highly scalable annotation, filtering, and analysis pipeline—gNOME—to prioritize phenotype‐associated variants while minimizing false‐positive findings. Intuitive graphical user interface of gNOME facilitates the selection of phenotype‐associated variants, and the result summaries are provided at variant, gene, and genome levels. Moreover, the enrichment results of specific variants, genes, and gene sets between two groups or compared with population scale WGS datasets that is already integrated in the pipeline can help the interpretation. We found a small number of discordant results between annotation software tools in part due to different reporting strategies for the variants with complex impacts. Using two published whole‐exome datasets of uveal melanoma and bladder cancer, we demonstrated gNOME's accuracy of variant annotation and the enrichment of loss‐of‐function variants in known cancer pathways. gNOME Web server and source codes are freely available to the academic community ( http://gnome.tchlab.org ).     

No association of genetic variants in BDNF with major depression: A meta‐ and gene‐based analysis

Major depressive disorder (MDD) is a complex psychiatric condition with strong genetic predisposition. The association of MDD with genetic polymorphisms, such as Val66Met (rs6265), in the brain derived neurotrophic factor (BDNF), have been reported in many studies and the results were conflicting. In this study, we performed a systematic literature search and conducted random‐effects meta‐analysis to evaluate genetic variants in BDNF with MDD. A gene‐based analysis was also conducted to investigate the cumulative effects of genetic polymorphisms in BDNF. A total of 28 studies from 26 published articles were included in our analysis. Meta‐analysis yielded an estimated odds ratio (OR) of 0.96 (95% CI: 0.89–1.05; P = 0.402) for Val66Met (rs6265), 0.83 (95% CI: 0.67–1.04; P = 0.103) for 11757C/G, 1.16 (95% CI: 0.74–1.82; P = 0.527) for 270T/C, 1.03 (95% CI: 0.18–5.75; P = 0.974) for 712A/G and 0.98 (95% CI: 0.85–1.14; P = 0.831) for rs988748. The gene‐based analysis indicated that BDNF is not associated with MDD (P > 0.21). Our updated meta‐ and novel gene‐based analyses provide no evidence of the association of BDNF with major depression. © 2012 Wiley Periodicals, Inc.     

Meta‐analysis of association between obsessive‐compulsive disorder and the 3′ region of neuronal glutamate transporter gene SLC1A1

The neuronal glutamate transporter gene SLC1A1 is a candidate gene for obsessive‐compulsive disorder (OCD) based on linkage studies and convergent evidence implicating glutamate in OCD etiology. The 3′ end of SLC1A1 is the only genomic region with consistently demonstrated OCD association, especially when analyzing male‐only probands. However, specific allele associations have not been consistently replicated, and recent OCD genome‐wide association and meta‐analysis studies have not incorporated all previously associated SLC1A1 SNPs. To clarify the nature of association between SLC1A1 and OCD, pooled analysis was performed on all available relevant raw study data, comprising a final sample of 815 trios, 306 cases and 634 controls. This revealed weak association between OCD and one of nine tested SLC1A1 polymorphisms (rs301443; uncorrected P = 0.046; non‐significant corrected P). Secondary analyses of male‐affecteds only (N = 358 trios and 133 cases) demonstrated modest association between OCD and a different SNP (rs12682807; uncorrected P = 0.012; non‐significant corrected P). Findings of this meta‐analysis are consistent with the trend of previous candidate gene studies in psychiatry and do not clarify the putative role of SLC1A1 in OCD pathophysiology. Nonetheless, it may be important to further examine the potential associations demonstrated in this amalgamated sample, especially since the SNPs with modest associations were not included in the more highly powered recent GWAS or in a past meta‐analysis including five SLC1A1 polymorphisms. This study underscores the need for much larger sample sizes in future genetic association studies and suggests that next‐generation sequencing may be beneficial in examining the potential role of rare variants in OCD. © 2013 Wiley Periodicals, Inc.     

Phylogenetic analysis of human G9P[8] rotavirus strains circulating in Jiangsu,China between 2010 and 2016

Rotavirus A (RVA) is the leading cause of acute viral gastroenteritis in children under 5 years of age worldwide. G9P[8] is a common RVA genotype that has been persistently prevalent in Jiangsu, China. To determine the genetic diversity of G9P[8] RVAs, 7 representative G9P[8] strains collected from Suzhou Children’s Hospital between 2010 and 2016 (named JS2010‐JS2016) were analyzed through whole‐genome sequencing. All evaluated strains showed the Wa‐like constellation G9‐P[8]‐I1‐R1‐C1‐M1‐A1‐N1‐T1‐E1‐H1. Furthermore, phylogenetic analysis revealed that the VP7 genes of all strains clustered into lineage G9‐III and G9‐VI. With the exception of strain JS2012 (P[8]‐4), the VP4 sequences of all strains belonged to the P[8]‐3 lineage. Sequencing further revealed that amino acid substitutions were present in the antigenic regions of the VP7 and VP4 genes of all strains. Moreover, there were multiple substitutions in antigenic sites I and II of the nonstructural protein 4 (NSP4) genes, whereas the other NSP genes were relatively conserved. In conclusion, our phylogenetic analysis of these 7 G9P[8] strains suggests that RVA varied across regions and time. Therefore, our findings suggest that continued surveillance is necessary to explore the molecular evolutionary characteristics of RVA for better prevention and treatment of acute viral gastroenteritis.     

Interdisciplinary medical, nursing, and administrator education in practice: the Johns Hopkins experience.

Reforming graduate medical, nursing and health administrators' education to include the core competencies of interdisciplinary teamwork and quality improvement (QI) techniques is a key strategy to improve quality in hospital settings. Practicing clinicians are best positioned in these settings to understand systems issues and craft potential solutions. The authors describe how, in ten months during 2004 and 2005 the school of medicine, the school of nursing, and an administrative residency program, all at Johns Hopkins University, implemented and evaluated the Achieving Competency Today II Program (ACT II), a structured and interdisciplinary approach to learning QI that was piloted at various sites around the United States. Six teams of learners participated, each consisting of a medical, nursing, and administrative resident.The importance of interdisciplinary participation in planning QI projects, the value of the patient's perspective on systems issues, and the value of a system's perspective in crafting solutions to issues all proved to be valuable lessons. Challenges were encountered throughout the program, such as (1) participants' difficulties in balancing competing academic, personal and clinical responsibilities, (2) difficulties in achieving the intended goals of a broad curriculum, (3) barriers to openly discussing interdisciplinary team process and dynamics, and (4) the need to develop faculty expertise in systems thinking and QI. In spite of these challenges steps have been identified to further enhance and develop interdisciplinary education within this academic setting.     

Analysis of Family‐ and Population‐Based Samples Using Multiple Linkage Disequilibrium Mapping

We report two methods for linkage disequilibrium mapping that involve incorporation of covariates through parametric modeling to utilize combined case‐parent trios and unrelated case and/or control data. The proposed two combined methods were used to map the disease locus of hypertension in the angiotensin‐converting enzyme (ACE) gene with incorporation of ACE activity. The efficiencies in estimating the disease locus increased by 351‐ and 100‐fold in the hybrid study with respect to the two proposed methods when compared to the estimates from the trios study; and they changed by 1.4‐ and 0.4‐fold, respectively, when compared to the case‐control study. Efficiency of disease locus estimates was greatly improved in both simulations and hypertension studies based on the hybrid data, compared to case‐parent trio studies only. These newly developed methods preserve the advantages of the previous methods, including flexible modeling and assessment of gene‐gene and gene‐covariate effects, while providing more power by using all the data combined. The computing program for analysis using the separate and hybrid data sets is freely available on the author's website.     

Clinical and molecular characterization of Indian patients with fructose‐1, 6‐bisphosphatase deficiency: Identification of a frequent variant (E281K)

Fructose‐1, 6‐bisphosphatase deficiency is an autosomal recessive disorder of gluconeogenesis caused by genetic defect in the FBP1 gene. It is characterized by episodic, often life‐threatening metabolic acidosis, liver dysfunction, and hyperlactatemia. Without a high index of suspicion, it may remain undiagnosed with devastating consequences. Accurate diagnosis can be achieved either by enzyme assay or gene studies. Enzyme assay requires a liver biopsy and is tedious, invasive, expensive, and not easily available. Therefore, genetic testing is the most appropriate method to confirm the diagnosis. Molecular studies were performed on 18 suspected cases presenting with episodic symptoms. Seven different pathogenic variants were identified. Two common variants were noted in two subpopulations from the Indian subcontinent; p.Glu281Lys (E281K) occurred most frequently (in 10 patients) followed by p.Arg158Trp (R158W, in 4 patients). Molecular analysis confirmed the diagnosis and helped in managing these patients by providing appropriate genetic counseling. In conclusion, genetic studies identified two common variants in the Indian subcontinent, thus simplifying the diagnostic algorithm in this treatable disorder.     

Semi‐automated cancer genome analysis using high‐performance computing

Next‐generation sequencing (NGS) has turned from a new and experimental technology into a standard procedure for cancer genome studies and clinical investigation. While a multitude of software packages for cancer genome data analysis have been made available, these need to be combined into efficient analytical workflows that cover multiple aspects relevant to a clinical environment and that deliver handy results within a reasonable time frame. Here, we introduce QuickNGS Cancer as a new suite of bioinformatics pipelines that is focused on cancer genomics and significantly reduces the analytical hurdles that still limit a broader applicability of NGS technology, particularly to clinically driven research. QuickNGS Cancer allows a highly efficient analysis of a broad variety of NGS data types, specifically considering cancer‐specific issues, such as biases introduced by tumor impurity and aneuploidy or the assessment of genomic variations regarding their biomedical relevance. It delivers highly reproducible analysis results ready for interpretation within only a few days after sequencing, as shown by a reanalysis of 140 tumor/normal pairs from The Cancer Genome Atlas (TCGA) in which QuickNGS Cancer detected a significant number of mutations in key cancer genes missed by a well‐established mutation calling pipeline. Finally, QuickNGS Cancer obtained several unexpected mutations in leukemias that could be confirmed by Sanger sequencing.     

Expanding non‐invasive prenatal testing beyond chromosomes 21, 18, 13, X and Y

Non‐invasive prenatal testing (NIPT) based on cell‐free DNA in maternal plasma is being expanded to include additional chromosome abnormalities beyond those involving chromosomes 21, 18, 13, X and Y. Review of population cytogenetic data provides insight into the likely number of additional abnormalities detectable. Additional clinically significant and cytogenetically recognizable abnormalities are present in less than 0.1% of newborns but clinically significant, or potentially significant, sub‐microscopic imbalances are expected to be present in 1.7%. Cytogenetic studies on chorionic villus samples suggests that after excluding abnormalities involving chromosomes 21, 18, 13, X and Y, approximately 0.6% of NIPT results may be positive for an unbalanced abnormality attributable to mosaicism but most of these will not be confirmed at amniocentesis or in newborns. NIPT has also been developed for specific microdeletion syndromes and initial experience is now available. Laboratory procedures such as deeper sequencing and additional data analytics are rapidly evolving but even with existing protocols, it is already clear that NIPT does not necessarily need to be limited to trisomies 21, 18, 13 and the sex‐chromosome abnormalities. Patient educational materials and genetic counseling services need to be available for women offered expanded NIPT.     

Call for a Multidisciplinary Effort to Map the Lymphatic System with Advanced Medical Imaging Techniques: A Review of the Literature and Suggestions for Future Anatomical Research

This review intends to rekindle efforts to map the lymphatic system by using a more modern approach, based on medical imaging. The structure, function, and pathologies associated with the lymphatic system are first discussed to highlight the need for more accurately mapping the lymphatic system. Next, the need for an interdisciplinary approach, with a central role for the anatomist, to come up with better maps of the lymphatic system is emphasized. The current approaches on lymphatic system research involving medical imaging will be discussed and suggestions will be made for an all-encompassing effort to thoroughly map the entire lymphatic system. A first-hand account of our integration as anatomists in the radiotherapy department is given as an example of interdisciplinary collaboration. From this account, it will become clear that the interdisciplinary collaboration of anatomists in the clinical disciplines involved in lymphatic system research/treatment still holds great promise in terms of improving clinical regimens that are currently being employed. As such, we hope that our fellow anatomists will join us in an interdisciplinary effort to map the lymphatic system, because this could, in a relatively short timeframe, provide improved treatment options for patients with cancer or lymphatic pathologies all over the world. Anat Rec, 302:1681–1695, 2019. © 2019 American Association for Anatomy     

Genetic Factors in Nonsmokers with Age‐Related Macular Degeneration Revealed Through Genome‐Wide Gene‐Environment Interaction Analysis

Relatively little is known about the interaction between genes and environment in the complex etiology of age‐related macular degeneration (AMD). This study aimed to identify novel factors associated with AMD by analyzing gene‐smoking interactions in a genome‐wide association study of 1207 AMD cases and 686 controls of Caucasian background with genotype data on 668,238 single nucleotide polymorphisms (SNPs) after quality control. Participants’ history of smoking at least 100 cigarettes lifetime was determined by a self‐administered questionnaire. SNP associations modeled the effect of the minor allele additively on AMD using logistic regression, with adjustment for age, sex, and ever/never smoking. Joint effects of SNPs and smoking were examined comparing a null model containing only age, sex, and smoking against an extended model including genotypic and interaction terms. Genome‐wide significant main effects were detected at three known AMD loci: CFH (P = 7.51×10^?30), ARMS2 (P = 1.94×10^?23), and RDBP/CFB/C2 (P = 4.37×10^?10), while joint effects analysis revealed three genomic regions with P < 10^?5. Analyses stratified by smoking found genetic associations largely restricted to nonsmokers, with one notable exception: the chromosome 18q22.1 intergenic SNP rs17073641 (between SERPINB8 and CDH7), more strongly associated in nonsmokers (OR = 0.57, P = 2.73 × 10^?5), with an inverse association among smokers (OR = 1.42, P = 0.00228), suggesting that smoking modifies the effect of some genetic polymorphisms on AMD risk.     

BOOK REVIEW: Preventing Childhood Disorders,Substance Abuse,and Delinquency

Discusses (a) what roles the specialty of clinical child psychology fulfills and how societal and professional changes have enhanced the need for the specialty, (b) how the field defines itself, (c) how models of training are conceptualized for the specialty, and (d) how some training programs implement specialty training with broad, interdisciplinary components. Clinical child psychology is a professional field of research and practice that, when adequate training is provided, properly deserves a places as a specialty.The dangers of overspecialization and narrowness are more likely present in traditional clinical (adult) psychology than in clinical child psychology, especially when the clinical child training is done in a broadly comprehensive and integrated manner.     

Transmission route and introduction of pandemic SARS‐CoV‐2 between China,Italy, and Spain

We present a phylodynamic and phylogeographic analysis of this new severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) virus in this report. A tree of maximum credibility was constructed using the 72 entire genome sequences of this virus, from the three countries (China, Italy, and Spain) available as of 26 March 2020 on the GISAID reference frame. To schematize the current SARS‐CoV‐2 migration scenario between and within the three countries chosen, using the multitype bearth‐death model implemented in BEAST2. Bayesian phylogeographic reconstruction shows that SARS‐CoV‐2 has a rate of evolution of 2.11 × 10^?3 per sites per year (95% highest posterior density: 1.56 × 10^?3 to 3.89 × 10^?3), and a geographic origin in Shanghai, where time until the most recent common ancestor (tMRCA) emerged, according to the analysis of the molecular clock, around 13 November 2019. While for Italy and Spain, there are two tMRCA for each country, which agree with the assumption of several introductions for these countries. That explains also this very short period of subepidermal circulation before the recent events. A total of 8 (median) migration events occurred during this short period, the largest proportion of which (6 events [75%]) occurred from Shanghai (China) to Spain and from Italy to Spain. Such events are marked by speeds of migration that are comparatively lower as compared with that from Shanghai to Italy. Shanghai's R₀ and Italy's are closer to each other, though Spain's is slightly higher. All these results allow us to conclude the need for an automatic system of mixed, molecular and classical epidemiological surveillance, which could play a role in this global surveillance of public health and decision‐making.     

Comparison of X‐chromosome inactivation in Duchenne muscle/myocardium‐manifesting carriers,non‐manifesting carriers and related daughters

Female carriers of Duchenne muscular dystrophy (DMD) are usually asymptomatic. However, 2.5–7.8% of them may present muscle symptoms and cardiomyopathy, attributed to a reduced production of dystrophin, probably because of skewed patterns of X‐chromosome inactivation (XCI). To evaluate the role of XCI in symptomatic (at muscle or heart level) and asymptomatic DMD carriers, 44 subjects were selected from our database (12 manifesting, 21 non‐manifesting, 11 healthy females), and XCI pattern determined in the lymphocytes by the androgen receptor methylation‐based assay. The results showed that DMD‐manifesting carriers had a preferential inactivation of the X‐chromosome carrying the normal allele, while non‐manifesting carriers and healthy females showed a random XCI pattern. Moreover, when comparing muscle with heart manifesting carriers, the former group showed a higher degree of skewing. No concordance in XCI was found between mothers and daughters, when symptomatic/asymptomatic mother–daughter pairs were analyzed. The results confirm that DMD clinical manifestations in carriers are associated with non‐random patterns of X inactivation.     

Molecular epidemiology of recent HIV‐1 infections in southern Poland

The genetic diversity of human immunodeficiency virus type 1 (HIV‐1) offers an opportunity to track the development of the epidemic across different populations. Viral pol gene fragments from 55 individuals of Polish origin with recent HIV‐1 infection identified in 2008–2010 in four Polish cities were analyzed. Viral sequences were compared with sequences from 100 individuals (reference group) infected before 2004. Viral spread among groups with different HIV transmission categories was compared using a phylogenetic approach. The majority of sequences from individuals with recent infection were subtype B (93%) within which four transmission clusters (18% of samples) were detected. Samples from men infected through sex between men and from persons infected through injecting drugs were broadly separated (P < 0.0001), while samples from individuals infected by heterosexual contacts were dispersed uniformly within phylogenetic tree (P = 0.244) inferred from viral sequences derived from individuals infected recently and the reference group. The percentage of samples from persons infected by heterosexual contacts which clustered with samples from men infected through sex between men was not significantly higher for those with recent infection (47%), compared to the reference group (36%). In conclusion, men infected by sex between men and individuals infected through injecting drugs appear to form separate HIV transmission networks in Poland. The recent spread of HIV‐1 among persons infected with subtype B by heterosexual contacts appears to be linked to both these groups. J. Med. Virol. 84:1857–1868, 2012. © 2012 Wiley Periodicals, Inc.     

Self‐compassion,trauma, and posttraumatic stress disorder: A systematic review

Self‐compassion has emerged as an important construct in the mental health literature. Although conceptual links between self‐compassion and trauma are apparent, a review has not been completed to examine whether this association is supported by empirical research findings. To systematically summarize knowledge on the association between trauma and/or posttraumatic stress disorder (PTSD) and self‐compassion. Searches were conducted in PsycINFO, PubMed, Ovid Medline, Web of Science, Embase, and PILOTS databases, and papers reporting a direct analysis on the relationship between these constructs were identified. The search yielded 35 studies meeting inclusion criteria. Despite considerable heterogeneity in study design, sample, measurement, and trauma type, there was consistent evidence to suggest that increased self‐compassion is associated with less PTSD symptomatology and some evidence to suggest that reduced fear of self‐compassion is associated with less PTSD symptomatology. There was tentative evidence to suggest that interventions based, in part or whole, on a self‐compassion model potentially reduce PTSD symptoms. Although findings are positive for the association between increased self‐compassion and reduced PTSD symptoms, the precise mechanism of these protective effects is unknown. Prospective and longitudinal studies would be beneficial in clarifying this. The review also highlighted the variability in what is and should be referred to as trauma exposure, indicating the need for further research to clarify the concept.