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Supplemental Table 1: Identified NF1 variants; Supplemental Table 2: Tumors with multiple NF1 mutations include splice site, missense, nonsense, and frameshift mutations; Supplemental Table 3: KRAS mutations identified by next-generation sequencing.

Increasing rates of human papillomavirus (HPV)–driven oropharyngeal cancer (OPC) have largely offset declines in tobacco-associated head and neck squamous cell carcinoma (HNSCC) at non-OPC sites. Host immunity is an important modulator of HPV infection, persistence, and clearance, and also of immune evasion in both virally- and nonvirally-driven cancers. However, the association between collective known cancer-related immune gene variants and HNSCC susceptibility has not been fully characterized. Here, we conducted a genetic association study in the multiethnic Veterans Affairs Million Veteran Program cohort, evaluating 16,050 variants in 1,576 immune genes in 4,012 HNSCC cases (OPC = 1,823; non-OPC = 2,189) and 16,048 matched controls. Significant polymorphisms were further examined in a non-Hispanic white (NHW) validation cohort (OPC = 1,206; non-OPC = 955; controls = 4,507). For overall HNSCC susceptibility in NHWs, we discovered and validated a novel 9q31.1 SMC2 association and replicated the known 6p21.32 HLA-DQ-DR association. Six loci/genes for overall HNSCC susceptibility were selectively enriched in African-Americans (6p21.32 HLA-G, 9q21.33 GAS1, 11q12.2 CD6, 11q23.2 NCAM1/CD56, 17p13.1 CD68, 18q22.2 SOCS6); all 6 genes function in antigen-presenting regulation and T-cell activation. Two additional loci (10q26 DMBT1, 15q22.2 TPM1) were uncovered for non-OPC susceptibility, and three loci (11q24 CRTAM, 16q21 CDH5, 18q12.1 CDH2) were identified for HPV-positive OPC susceptibility. This study underscores the role of immune gene variants in modulating susceptibility for both HPV-driven and non-HPV-driven HNSCC. Additional large studies, particularly in racially diverse populations, are needed to further validate the associations and to help elucidate other potential immune factors and mechanisms that may underlie HNSCC risk.Significance:Several inherited variations in immune system genes are significantly associated with susceptibility to head and neck cancer, which could help improve personalized cancer risk estimates.

Increasing rates of human papillomavirus (HPV)–driven oropharyngeal cancer (OPC) have largely offset declines in tobacco-associated head and neck squamous cell carcinoma (HNSCC) at non-OPC sites. Host immunity is an important modulator of HPV infection, persistence, and clearance, and also of immune evasion in both virally- and nonvirally-driven cancers. However, the association between collective known cancer-related immune gene variants and HNSCC susceptibility has not been fully characterized. Here, we conducted a genetic association study in the multiethnic Veterans Affairs Million Veteran Program cohort, evaluating 16,050 variants in 1,576 immune genes in 4,012 HNSCC cases (OPC = 1,823; non-OPC = 2,189) and 16,048 matched controls. Significant polymorphisms were further examined in a non-Hispanic white (NHW) validation cohort (OPC = 1,206; non-OPC = 955; controls = 4,507). For overall HNSCC susceptibility in NHWs, we discovered and validated a novel 9q31.1 SMC2 association and replicated the known 6p21.32 HLA-DQ-DR association. Six loci/genes for overall HNSCC susceptibility were selectively enriched in African-Americans (6p21.32 HLA-G, 9q21.33 GAS1, 11q12.2 CD6, 11q23.2 NCAM1/CD56, 17p13.1 CD68, 18q22.2 SOCS6); all 6 genes function in antigen-presenting regulation and T-cell activation. Two additional loci (10q26 DMBT1, 15q22.2 TPM1) were uncovered for non-OPC susceptibility, and three loci (11q24 CRTAM, 16q21 CDH5, 18q12.1 CDH2) were identified for HPV-positive OPC susceptibility. This study underscores the role of immune gene variants in modulating susceptibility for both HPV-driven and non-HPV-driven HNSCC. Additional large studies, particularly in racially diverse populations, are needed to further validate the associations and to help elucidate other potential immune factors and mechanisms that may underlie HNSCC risk. Significance: Several inherited variations in immune system genes are significantly associated with susceptibility to head and neck cancer, which could help improve personalized cancer risk estimates.

Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide.To benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to explore associations between PRS and broad categories of human disease via phenome-wide association studies.Extensive Veterans Health Administration's electronic health records were assessed from October 1999 to January 2021, and an embedded cohort of 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder were found. The performance of schizophrenia, bipolar disorder, and major depression PRSs were compared in participants of African or European ancestry in the Million Veteran Program (approximately 400 000 individuals), and associations between PRSs and 1650 disease categories based on ICD-9/10 billing codes were explored. Last, genomic structural equation modeling was applied to derive novel PRSs indexing common and disorder-specific genetic factors. Analysis took place from January 2021 to January 2022.Diagnoses based on in-person structured clinical interviews were compared with ICD-9/10 billing codes. PRSs were constructed using summary statistics from genome-wide association studies of schizophrenia, bipolar disorder, and major depression.Of 707 299 enrolled study participants, 459 667 were genotyped at the time of writing; 84 806 were of broadly African ancestry (mean [SD] age, 58 [12.1] years) and 314 909 were of broadly European ancestry (mean [SD] age, 66.4 [13.5] years). Among 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder, 8962 (95.6%) were correctly identified using ICD-9/10 codes (2 or more). Among those of European ancestry, PRSs were robustly associated with having received a diagnosis of schizophrenia (odds ratio [OR], 1.81 [95% CI, 1.76-1.87]; P 10-257) or bipolar disorder (OR, 1.42 [95% CI, 1.39-1.44]; P 10-295). Corresponding effect sizes in participants of African ancestry were considerably smaller for schizophrenia (OR, 1.35 [95% CI, 1.29-1.42]; P 10-38) and bipolar disorder (OR, 1.16 [95% CI, 1.11-1.12]; P 10-10). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems.Using diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRSs, the validity of an electronic health records-based phenotyping approach in US veterans was demonstrated, highlighting the potential of PRSs for disentangling biological and mediated pleiotropy.

This paper aims to design the full-order and reduced-order fault detection filters (FDFs) under unified linear matrix inequality (LMI) conditions for polytopic uncertain discrete-time singular Markovian jump systems (DTSMJSs) with time-varying delays. The highlight of this work lies in that the designed full-order and reduced-order FDFs are suitable for four different state transition probability matrices (TPMs), and the reduced-order fault detection filter (FDF) not only meets fault detection (FD) sensitivity conditions of the complex systems but also improve the efficiency of FD. With the help of the Lyapunov function theory and convex polyhedron technique, a sufficient condition is presented to ensure that the singular model error augmented system is stochastically admissible with a prescribed H∞ performance index. Finally, two numerical examples are provided to illustrate the effectiveness of the proposed design method.

The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect biosamples with consent from at least one million veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records, make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide a genome-wide scan of the entire cohort, in parallel with whole-genome sequencing, methylation, and other ‘omics assays. Here, we present the design and performance of the MVP 1.0 custom Axiom array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality-control analysis was developed and conducted on an initial tranche of 485,856 individuals, leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high-quality genotypes not only on common variants but also on rare variants. We confirmed that, with non-European individuals making up nearly 30%, MVP’s substantial ancestral diversity surpasses that of other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current dataset has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.

Post-traumatic stress disorder (PTSD) is a major problem among military veterans and civilians alike, yet its pathophysiology remains poorly understood. We performed a genome-wide association study and bioinformatic analyses, which included 146,660 European Americans and 19,983 African Americans in the US Million Veteran Program, to identify genetic risk factors relevant to intrusive reexperiencing of trauma, which is the most characteristic symptom cluster of PTSD. In European Americans, eight distinct significant regions were identified. Three regions had values of P

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization (MR) analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2: P=1.6×10−6, IFNAR2: P=9.8×10−11, and IL-10RB: P=1.9×10−14) using cis-eQTL genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared eQTL signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.

Background Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world’s population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. Methods We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. Results Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10–30) and African American (P < .0005) participants in CSP #572. Conclusions We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.

This paper proposes a novel full-order and reduced-order fault detection filters (FDFs) design method for singular continuous-time Markovian jump systems (SCTMJSs) with completely known transition rates (TRs). In order to strengthen the reliability of full-order and reduced-order (FDFs), we incorporates the idea of congruent transformation Lyapunov matrix to solve the convex optimization problem. The superiority of this kind of design method is that shows full-order and reduced-order FDFs can be expressed by an inequality and effective. Particularly necessary to point out that the reduced-order fault detection filter (FDF) has fewer variables and shortens the time of fault detection (FD) compared with full-order FDF. At the end of this paper, an illustrative simulation example is given to verify the effectiveness of the proposed method.

The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect consented biosamples from at least one million Veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide genome-wide scan of the entire cohort, in parallel with whole genome sequencing, methylation, and other omics assays. Here, we present the design and performance of MVP 1.0 custom Axiom® array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality control analysis was developed and conducted on an initial tranche of 485,856 individuals leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high quality genotypes not only on common variants but also on rare variants. We confirmed the substantial ancestral diversity of MVP with nearly 30% non-European individuals, surpassing other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current data set has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.

This paper investigates the problem of full-order and reduced-order fault detection filter (FDF) design under unified linear matrix inequality (LMI) conditions for a class of continuous-time singular Markovian jump systems (CTSMJSs) with time-varying delays and polytopic uncertain transition rates. By constructing a new Lyapunov function, sufficient conditions are firstly provided for the singular model error augmented system such that the system is stochastically admissible with an H∞ performance level γ. And then, by applying a novel convex polyhedron technique to decoupled linear matrix inequalities, the full-order and reduced-order fault detection filter parameters can be obtained within a convex optimization frame. The reduced-order fault detection filter (FDF) can not only meet the fault detection accuracy requirements of complex systems but also improve the fault detection efficiency. Finally, a DC motor and an illustrative simulation example are given to verify the feasibility and effectiveness of the proposed algorithms.

BackgroundHabitual alcohol use can be an indicator of alcohol dependence, which is associated with a wide range of serious health problems.MethodsWe completed a genome-wide association study in 126,936 European American and 17,029 African American subjects in the Veterans Affairs Million Veteran Program for a quantitative phenotype based on maximum habitual alcohol consumption.ResultsADH1B, on chromosome 4, was the lead locus for both populations: for the European American sample, rs1229984 (p= 4.9× 10-47); for African American, rs2066702 (p= 2.3× 10-12). In the European American sample, we identified three additional genome-wide-significant maximum habitual alcohol consumption loci: on chromosome 17, rs77804065 (p= 1.5× 10-12), at CRHR1 (corticotropin-releasing hormone receptor 1); the protein product of this gene is involved in stress and immune responses; and on chromosomes 8 and 10. European American and African American samples were then meta-analyzed; the associated region at CRHR1 increased in significance to 1.02× 10-13, and we identified two additional genome-wide significant loci, FGF14 (p= 9.86× 10-9) (chromosome 13) and a locus on chromosome 11. Besides ADH1B, none of the five loci have prior genome-wide significant support. Post-genome-wide association study analysis identified genetic correlation to other alcohol-related traits, smoking-related traits, and many others. Replications were observed in UK Biobank data. Genetic correlation between maximum habitual alcohol consumption and alcohol dependence was 0.87 (p= 4.78× 10-9). Enrichment for cell types included dopaminergic and gamma-aminobutyric acidergic neurons in midbrain, and pancreatic delta cells.ConclusionsThe present study supports five novel alcohol-use risk loci, with particularly strong statistical support for CRHR1. Additionally, we provide novel insight regarding the biology of harmful alcohol use.

We live in the genomic era of medicine, where a patient's genomic/molecular data is becoming increasingly important for disease diagnosis, identification of targeted therapy, and risk assessment for adverse reactions. However, decoding the genomic test results and integrating it with clinical data for retrospective studies and cohort identification for prospective clinical trials is still a challenging task. In order to overcome these barriers, we developed an overarching enterprise informatics framework for translational research and personalized medicine called Synergistic Patient and Research Knowledge Systems (SPARKS) and a suite of tools called Oncology Data Retrieval Systems (OncDRS). OncDRS enables seamless data integration, secure and self-navigated query and extraction of clinical and genomic data from heterogeneous sources. Within a year of release, the system has facilitated more than 1500 research queries and has delivered data for more than 50 research studies.

The physics related to superhydrophobic surfaces has been investigated with attention of its potential applications in a variety of industrial and scientific fields. In the present study, a coralloid superhydrophobic coating with numerous nanometer-scale embossments has been fabricated on the filter paper surface by a simple, facile and inexpensive route. The observations show that the wettability of paper sample has been transformed from superhydrophilicity to superhydrophobicity with the WCA of 156°, and had no significant change under ambient condition or in the water, oil and corrosive liquids, displaying an outstanding superhydrophobic stability. Importantly, the coated paper sample possesses not only superhydrophobicity but also superoleophobicity, and presents an excellent property in water–oil separation, which offers an opportunity to extend the range of practical applications for filter paper.

Purpose: NF1 is a tumor suppressor that negatively regulates Ras signaling. NF1 mutations occur in lung cancer, but their clinical significance is unknown. We evaluated clinical and molecular characteristics of NF1 mutant lung cancers with comparison to tumors with KRAS mutations. Experimental Design: Between July 2013 and October 2014, 591 non–small cell lung cancer (NSCLC) tumors underwent targeted next-generation sequencing in a 275 gene panel that evaluates gene mutations and genomic rearrangements. NF1 and KRAS cohorts were identified, with subsequent clinical and genomic analysis. Results: Among 591 patients, 60 had NF1 mutations (10%) and 141 (24%) had KRAS mutations. 15 NF1 mutations (25%) occurred with other oncogenic mutations [BRAF (2); ERBB2 (2); KRAS (9); HRAS (1); NRAS (1)]. There were 72 unique NF1 variants. NF1 tumor pathology was diverse, including both adenocarcinoma (36, 60%) and squamous cell carcinoma (10, 17%). In contrast, KRAS mutations occurred predominantly in adenocarcinoma (136, 96%). Both mutations were common in former/current smokers. Among NF1 tumors without concurrent oncogenic alterations, TP53 mutations/2-copy deletions occurred more often (33, 65%) than with KRAS mutation (46, 35%; P < 0.001). No difference between cohorts was seen with other tumor suppressors. Conclusions: NF1 mutations define a unique population of NSCLC. NF1 and KRAS mutations present in similar patient populations, but NF1 mutations occur more often with other oncogenic alterations and TP53 mutations. Therapeutic strategies targeting KRAS activation, including inhibitors of MAP kinase signaling, may warrant investigation in NF1 mutant tumors. Tumor-suppressor inactivation patterns may help further define novel treatment strategies. Clin Cancer Res; 22(13); 3148–56. ©2016 AACR.

MicroRNAs have essential functional roles in brain development and neuronal specification but their roles in neurode- generative diseases such as Alzheimer's disease (AD) is unknown. Using a sensitive qRT-PCR platform we identified regional and stage-specific deregulation of miRNA expression in AD patient brains. We used experimental validation in addition to literature to reveal how the deregulated brain microRNAs are biomarkers for known and novel pathways in AD pathogenesis related to amyloid processing, neurogenesis, insulin resistance, and innate immunity. We additionally recovered miRNAs from cerebrospinal fluid and discovered AD-specific miRNA changes consistent with their role as potential biomarkers of disease.

This paper is concerned with chaos induced by regular snap-back repellers. One new criterion of chaos induced by strictly coupled-expanding maps in compact sets of metric spaces is established. By employing this criterion, the nondegenerateness assumption in the Marotto theorem established in 1978 is weakened. In addition, it is proved that a regular snap-back repeller and a regular homoclinic orbit to a regular expanding fixed point in finite-dimensional spaces imply chaos in the sense of Li–Yorke. An illustrative example is provided with computer simulations.

8022 Background: NF1 is a tumor suppressor that negatively regulates Ras, thus NF1 mutant tumors may also be sensitive to inhibitors of MAP kinase signaling. NF1 variants occur in lung cancer, but ...

The availability of complete genome sequences enables all the members of a gene family to be identified without limitations imposed by temporal, spatial or quantitative aspects of mRNA expression. Using the nearly completed human genome sequence, we combined in silico and experimental approaches to define the complete human nuclear receptor (NR) set. This information was used to carry out a comparative genomic study of the NR superfamily. Our analysis of the human genome identified two novel NR sequences. Both these contained stop codons within the coding regions, indicating that both are pseudogenes. One (HNF4 γ-related) contained no introns and expressed no detectable mRNA, whereas the other (FXR-related) produced mRNA at relatively high levels in testis. If translated, the latter is predicted to encode a short, non-functional protein. Our analysis indicates that there are fewer than 50 functional human NRs, dramatically fewer than in Caenorhabditis elegans and about twice as many as in Drosophila. Using the complete human NR set we made comparisons with the NR sets of C. elegans and Drosophila. Searches for the >200 NRs unique to C. elegans revealed no human homologs. The comparative analysis also revealed a Drosophila member of NR subfamily NR3, confirming an ancient metazoan origin for this subfamily. This work provides the basis for new insights into the evolution and functional relationships of NR superfamily members.