MATS: a novel multi-ancestry transcriptome-wide association study to account for heterogeneity in the effects of cis-regulated gene expression on complex traits.

The Transcriptome-Wide Association Study (TWAS) is a widely used approach which integrates gene expression and Genome Wide Association Study (GWAS) data to study the role of cis-regulated gene expression (GEx) in complex traits. However, the genetic architecture of GEx varies across populations, and recent findings point to possible ancestral heterogeneity in the effects of GEx on complex traits, which may be amplified in TWAS by modeling GEx as a function of cis-eQTLs. Here, we present a novel extension to TWAS to account for heterogeneity in the effects of cis-regulated GEx which are correlated with ancestry. Our proposed Multi-Ancestry TwaS (MATS) framework jointly analyzes samples from multiple populations and distinguishes between shared, ancestry-specific and/or subject-specific expression-trait associations. As such, MATS amplifies power to detect shared GEx associations over ancestry-stratified TWAS through increased sample sizes, and facilitates the detection of genes with subgroup-specific associations which may be masked by standard TWAS. Our simulations highlight the improved Type-I error conservation and power of MATS compared with competing approaches. Our real data applications to Alzheimer's disease (AD) case-control genotypes from the Alzheimer's Disease Sequencing Project (ADSP) and continuous phenotypes from the UK Biobank (UKBB) identify a number of unique gene-trait associations which were not discovered through standard and/or ancestry-stratified TWAS. Ultimately, these findings promote MATS as a powerful method for detecting and estimating significant gene expression effects on complex traits within multi-ancestry cohorts and corroborates the mounting evidence for inter-population heterogeneity in gene-trait associations.

Accounting for nonlinear effects of gene expression identifies additional associated genes in transcriptome-wide association studies.

Transcriptome-wide association studies (TWAS) integrate genome-wide association study (GWAS) data with gene expression (GE) data to identify (putative) causal genes for complex traits. There are two stages in TWAS: in Stage 1, a model is built to impute gene expression from genotypes, and in Stage 2, gene-trait association is tested using imputed gene expression. Despite many successes with TWAS, in the current practice, one only assumes a linear relationship between GE and the trait, which however may not hold, leading to loss of power. In this study, we extend the standard TWAS by considering a quadratic effect of GE, in addition to the usual linear effect. We train imputation models for both linear and quadratic gene expression levels in Stage 1, then include both the imputed linear and quadratic expression levels in Stage 2. We applied both the standard TWAS and our approach first to the ADNI gene expression data and the IGAP Alzheimer's disease GWAS summary data, then to the GTEx (V8) gene expression data and the UK Biobank individual-level GWAS data for lipids, followed by validation with different GWAS data, suitable model checking and more robust TWAS methods. In all these applications, the new TWAS approach was able to identify additional genes associated with Alzheimer's disease, LDL and HDL cholesterol levels, suggesting its likely power gains and thus the need to account for potentially nonlinear effects of gene expression on complex traits.

Implicating causal brain imaging endophenotypes in Alzheimer's disease using multivariable IWAS and GWAS summary data.

Recent evidence suggests the existence of many undiscovered heritable brain phenotypes involved in Alzheimer's Disease (AD) pathogenesis. This finding necessitates methods for the discovery of causal brain changes in AD that integrate Magnetic Resonance Imaging measures and genotypic data. However, existing approaches for causal inference in this setting, such as the univariate Imaging Wide Association Study (UV-IWAS), suffer from inconsistent effect estimation and inflated Type I errors in the presence of genetic pleiotropy, the phenomenon in which a variant affects multiple causal intermediate risk phenotypes. In this study, we implement a multivariate extension to the IWAS model, namely MV-IWAS, to consistently estimate and test for the causal effects of multiple brain imaging endophenotypes from the Alzheimer's Disease Neuroimaging Initiative (ADNI) in the presence of pleiotropic and possibly correlated SNPs. We further extend MV-IWAS to incorporate variant-specific direct effects on AD, analogous to the existing Egger regression Mendelian Randomization approach, which allows for testing of remaining pleiotropy after adjusting for multiple intermediate pathways. We propose a convenient approach for implementing MV-IWAS that solely relies on publicly available GWAS summary data and a reference panel. Through simulations with either individual-level or summary data, we demonstrate the well controlled Type I errors and superior power of MV-IWAS over UV-IWAS in the presence of pleiotropic SNPs. We apply the summary statistic based tests to 1578 heritable imaging derived phenotypes (IDPs) from the UK Biobank. MV-IWAS detected numerous IDPs as possible false positives by UV-IWAS while uncovering many additional causal neuroimaging phenotypes in AD which are strongly supported by the existing literature.

Management of Acute Aortic Dissection During Critical Care Air Medical Transport.

Acute aortic dissection is a time-critical emergency that air medical teams must be capable of transporting. Aortic dissections can manifest a myriad of complications in which prompt recognition and tailored treatments may mitigate additional physiological burden and limit dissection flap propagation. The purpose of this review is to discuss specific critical scenarios that air medical providers may be faced with and to equip them with a pathophysiological understanding of the disease and best practices for the management of acute aortic dissections.

Chronic obstructive pulmonary disease upper airway microbiota alpha diversity is associated with exacerbation phenotype: a case-control observational study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) frequent exacerbators (FE) suffer increased morbidity and mortality compared to infrequent exacerbators (IE). The association between the oral and sputum microbiota and exacerbation phenotype is not well defined. The objective of this study was to determine key features that differentiate the oral and sputum microbiota of FEs from the microbiota of IEs during periods of clinical stability. METHODS: We recruited 11 FE and 11 IE who had not used antibiotics or systemic corticosteroids in the last 1 month. Subjects provided oral wash and sputum samples, which underwent 16S V4 MiSeq sequencing and qPCR of 16S rRNA. Data were analyzed using Dada2 and R. RESULTS: FE and IE were similar in terms of age, FEV1 percent predicted (FEV1pp), pack-years of tobacco exposure, and St. George's Respiratory Questionnaire score. 16S copy numbers were significantly greater in sputum vs. oral wash (p = 0.01), but phenotype was not associated with copy number. Shannon diversity was significantly greater in oral samples compared to sputum (p = 0.001), and IE samples were more diverse than FE samples (p < 0.001). Sputum samples from FE had more Haemophilus and Moraxella compared to IE sputum samples, due to dominance of these COPD-associated taxa in three FE sputum samples. Amplicon sequencing variant (ASV)-level analysis of sputum samples revealed one ASV (Actinomyces) was significantly more abundant in IE vs. FE sputum (padj = 0.048, Wilcoxon rank-sum test), and this persisted after controlling for FEV1pp. Principal coordinate analysis using Bray-Curtis distance with PERMANOVA analyses demonstrated clustering by anatomic site, phenotype, inhaled corticosteroid use, current tobacco use, COPD severity, and last professional dental cleaning. CONCLUSIONS: FE have less diverse oral and sputum microbiota than IE. Actinomyces was significantly more abundant in IE sputum than FE sputum. The oral and sputum microbiota of COPD subjects cluster based on multiple clinical factors, including exacerbation phenotype. Even during periods of clinical stability, the frequent exacerbator phenotype is associated with decreased alpha diversity, beta-diversity clustering, and changes in taxonomic abundance.

Medico-legal risk associated with pediatric mental health telephone consultation programs.

Clinicians providing consultation through mental health telephone consultation programs express concern about the potential legal risk of the practice. In this survey of six state mental health telephone consultation program directors, we report the annual number of children referred for consultation and the number of lawsuits against consultant clinicians. Between 2004 and 2010, 3,652 children per year were referred nationally, and there were no medical malpractice lawsuits against clinicians related to telephone consultation program activity. Although medico-legal risk is always present, the findings of this national study suggest the risk for clinicians providing mental health telephone consultation may be lower than perceived.

Leveraging omics data to boost the power of genome-wide association studies.

Genome-wide association studies (GWASs) have successfully identified many genetic variants and risk loci for complex traits and common diseases in the last 15 years. However, these identified variants, in general, can explain only a small to moderate proportion of the heritability, thus the task of improving GWAS power for more discoveries remains both critical and challenging. In addition to the usual but costly or even infeasible route of continuing to increase the sample size, many approaches have been proposed to incorporate functional annotations to prioritize SNPs but with only limited success. Here, by taking advantage of increasing availability of various types of omics data, we propose a new and orthogonal approach by integrating individual-level omics data with GWASs. The premise is that since omics data reflect both genetic and environmental (such as diet and other lifestyle) effects on individuals, they can be used to account for (otherwise unexplained) variations among individuals in GWAS analysis, leading to more precise/efficient estimation and thus higher power. As a concrete example, we propose boosting GWAS power by adjusting for metabolomics data in GWAS analysis. We applied the method to the UK Biobank subcohort of n = 90,000 individuals with both GWAS and metabolomics data. The analysis of 7 quantitative traits and one binary trait demonstrated clear power gains. For example, the new method (after adjusting for metabolomics data) identified 13 new loci for diastolic blood pressure that were all missed by the standard GWAS, and most or all of the 13 new signals were validated in two much larger GWAS datasets (n = 340,000 and 700,000); the improved estimation efficiency was equivalent to a 38.4% gain of GWAS sample size. The proposed method is both simple and promising and broadly applicable to integrating GWASs with other omics data.

Integrating brain imaging endophenotypes with GWAS for Alzheimer's disease.

Background: Genome wide association studies (GWAS) have identified many genetic variants associated with increased risk of Alzheimer's disease (AD). These susceptibility loci may effect AD indirectly through a combination of physiological brain changes. Many of these neuropathologic features are detectable via magnetic resonance imaging (MRI). Methods: In this study, we examine the effects of such brain imaging derived phenotypes (IDPs) with genetic etiology on AD, using and comparing the following methods: two-sample Mendelian randomization (2SMR), generalized summary statistics based Mendelian randomization (GSMR), transcriptome wide association studies (TWAS) and the adaptive sum of powered score (aSPU) test. These methods do not require individual-level genotypic and phenotypic data but instead can rely only on an external reference panel and GWAS summary statistics. Results: Using publicly available GWAS datasets from the International Genomics of Alzheimer's Project (IGAP) and UK Biobank's (UKBB) brain imaging initiatives, we identify 35 IDPs possibly associated with AD, many of which have well established or biologically plausible links to the characteristic cognitive impairments of this neurodegenerative disease. Conclusions: Our results highlight the increased power for detecting genetic associations achieved by multiple correlated SNP-based methods, i.e., aSPU, GSMR and TWAS, over MR methods based on independent SNPs (as instrumental variables).

Driving Access and Quality: A Shift to Value-Based Behavioral Health Care.

Multiple barriers exist to accessing behavioral health care, and several are related to payment. The national shortage of behavioral health providers is exacerbated by their not joining health insurance networks, often shifting the cost of treatment to patients. In the face of high out-of-network expenses, deductibles, and copays, many insured patients forgo behavioral health treatment altogether. However, even when patients access care, health outcomes are not routinely measured, and there is reason to suspect that the quality of care is poor. To address these issues, value-based reimbursement for behavioral health care offers a sustainable pathway to increase payment for providers in return for improved population health outcomes and costs. This article describes a comprehensive collaborative effort between a payer and a health care technology and services organization to support behavioral health providers to enter into value-based care. This approach changes financial incentives to drive improvements in behavioral health care access and quality.

Chronic obstructive pulmonary disease upper airway microbiome is associated with select clinical characteristics.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disorder associated with lung microbiome dysbiosis. Although the upper airway microbiome is the source of the lung microbiome, the relationships between the oral, nasal, and sputum microbiota are incompletely understood. Our objective was to determine features that differentiate the oral, nasal, and sputum microbiome among subjects with stable COPD. METHODS: We recruited 15 current or former smokers to provide oral and sputum samples on day 1. On day 2, another oral sample and a nasal sample were obtained. Each sample and control underwent DNA extraction, 16S V4 rRNA amplification, 16S V4 sequencing, and qPCR of 16S rRNA. Data were analyzed using dada2 and R. RESULTS: Most (14 of 15) subjects were male with a mean age of 65.2. One subject had no pulmonary obstruction, while 5 had mild COPD, 7 had moderate COPD, and 2 had severe COPD. Three subjects (20%) were current tobacco users and 2 subjects (13%) used inhaled corticosteroids (ICS). Subjects had a mean of 49.1 pack-years of tobacco exposure. Bacterial biomass was associated with anatomic site, but no differences in biomass were observed with age, FEV1 percent predicted (FEV1pp), ICS use, smoking status, or edentulous state. Shannon index was associated with site (lower nasal diversity than oral and sputum diversity, p<0.001), but not age, ICS use, FEV1pp, tobacco use, or edentulous state. ß-diversity was illustrated by principal coordinate analysis using Bray-Curtis dissimilarity and PERMANOVA analyses, showing sample clustering by anatomic site (p = 0.001) with nasal samples forming a cluster separate from the combined oral wash samples and sputum samples. Clustering was also observed with ICS use (p = 0.029) and edentulous state (p = 0.019), while FEV1pp and current tobacco use were not significant. In an amplicon sequencing variant (ASV)-level analysis of oral samples using a linear regression model with Benjamini-Hochberg correction at an FDR<0.10, 10 ASVs were associated with age while no ASVs were associated with FEV1pp or smoking status. Sputum sample analysis demonstrated that 51 ASVs (25 unique genera) were associated with age, 61 ASVs (32 genera) were associated with FEV1pp, and no ASVs were associated with smoking status. In a combined dataset, the frequent exacerbator phenotype, rather than ICS use, was associated with decreased sputum Shannon diversity. CONCLUSIONS: Among the upper airway microbiota of COPD subjects, anatomic site was associated with bacterial biomass, Shannon diversity, and ß-diversity. ICS use and edentulous state were both associated with ß-diversity. Age was associated with taxa relative abundance in oral and sputum samples, while FEV1pp was associated with taxa relative abundance in sputum samples only.

Care Coordination for Youth With Mental Health Disorders in Primary Care.

Many children are treated for mental health disorders in primary care settings. The system of care (SOC) provides a framework for collaboration among pediatric mental health providers, but it is unclear if youth treated for mental health disorders in primary care receive such coordination. At the South Boston Community Health Center from September /2012 to August 2013 for 74 individuals ≤18 years, the odds of contact with SOC agencies (mental health, education, child protective services, juvenile justice and developmental disabilities) were compared for mental health treatment in primary versus specialty care. The odds of SOC contact within primary care were lower compared to specialty care (OR = 0.43, 95% CI = 0.29-0.66), specifically for mental health (OR = 0.54, 95% CI = 0.25-1.2), education (OR = 0.12, 95% CI = 0.050-0.28), and child protective services (OR = 0.64, 95% CI = 0.22-1.9). As care coordination may improve health outcomes, increased support and education for care coordination specific to youth treated for mental health disorders in primary care settings may be warranted.

Payment for Integrated Care: Challenges and Opportunities.

A multidisciplinary team approach to care and robust care coordination services are primary components of almost all integrated care delivery systems. Given that these services have limited reimbursement in fee-for-service payment arrangements, integrating care in a fee-for-service environment is almost impossible. Capitated payment models hold promise for supporting integrated behavioral and physical health services. There are multiple national examples of integrated care delivery systems supported by capitated payment arrangements.

Preliminary Outcomes from an Integrated Pediatric Mental Health Outpatient Clinic.

An estimated 1 in 5 children in the United States meet criteria for a diagnosable mental disorder, yet fewer than 20% receive mental health services. Unmet need for psychiatric treatment may contribute to patterns of increasing use of the emergency department. This article describes an integrated pediatric evaluation center designed to prevent the need for treatment in emergency settings by increasing access to timely and appropriate care for emergent and critical mental health needs. Preliminary results showed that the center provided rapid access to assessment and treatment services for children and adolescents presenting with a wide range of psychiatric concerns.

Developing a Pipeline for the Community-Based Primary Care Workforce and Its Leadership: The Kraft Center for Community Health Leadership's Fellowship and Practitioner Programs.

PROBLEM: Community health centers (CHCs) face challenges recruiting and retaining primary care clinicians. Providing advanced training that enhances clinical skills within a public health framework, teaches leadership, protects time for scholarly activities, and focuses on the social mission may be a successful career development strategy. APPROACH: In July 2012, the Kraft Center for Community Health Leadership developed and implemented two 2-year programs to develop physician and nursing leaders with blended academic-community career paths and identities. The fellowship program for physicians and the practitioner program for early-career physicians and advanced practice nurses include mentored practice in a CHC; monthly learning days; completion of a community-based research project; and, for fellows, matriculation in an MPH program and engagement in a bimonthly leadership seminar. OUTCOMES: The first classes of 5 fellows and 14 practitioners graduated in June 2014. All 5 fellowship graduates were offered full-time positions at the CHCs where they practiced, and 2 have accepted leadership positions at their CHCs. All 14 practitioner graduates remain in community health, 5 have accepted leadership positions, and 2 have obtained grants to support ongoing projects. NEXT STEPS: The authors are tracking graduates' career paths and the programs' impact on CHCs while modifying the programs on the basis of feedback; identifying elements of the programs that may be amenable to more cost-effective delivery; and exploring the potential for federal funding to support expansion of the practitioner program, and for the practitioner program to increase the return on investment provided by the National Health Service Corps.

Clinicians' utilization of child mental health telephone consultation in primary care: findings from Massachusetts.

OBJECTIVE: The authors examined utilization of the Massachusetts Child Psychiatry Access Project, a mental health telephone consultation service for primary care, hypothesizing that greater use would be related to severe psychiatric diagnoses and polypharmacy. METHODS: The authors examined the association between utilization, defined as the mean number of contacts per patient during the 180 days following the initial contact (July 2008-June 2009), and characteristics of the initial contact, including consultation question, the child's primary mental health problem, psychotropic medication regimen, insurance status, and time of year. RESULTS: Utilization (N=4,436 initial contacts, mean=3.83 contacts) was associated with initial contacts about medication management, polypharmacy, public and private health insurance, and time of year. The child's primary mental health problem did not predict utilization. CONCLUSIONS: Telephone consultation services address treatment with psychotropic medications, particularly polypharmacy. Joint public-private funding should be considered for such public programs that serve privately insured children.